| Current
Protein & Peptide Science
ISSN: 1389-2037
Upcoming Articles
The Retinal cGMP Phosphodiesterase γ-Subunit
— A Chameleon
Lian-Wang Guoand Arnold E. Ruoho
[Abstract]
Into the Lipid Realm: Stability and Thermodynamics
of Membrane Proteins
Francisco N. Barrera, Luis A. Alcaraz, Estefanía
Hurtado-Gómez and José L. Neira,
[Abstract]
Advances and Pitfalls in Protein Structure Prediction
D. Cozzetto and A. Tramontano
[Abstract]
Flexible Structures and Ligand Interactions of Tandem
Repeats Consisting of Proline, Glycine, Asparagine, Serine,
and/or Threonine Rich Oligopeptides in Proteins
Norio Matsushima, Hitoshi Yoshida, Yasuhiro Kumaki,
Masakatsu Kamiya, Takanori Tanaka, Yoshinobu Izumi and Robert
H. Kretsinger
[Abstract]
Plasma Gelsolin: Function, Prognostic Value, and Potential
Therapeutic Use
Robert Bucki, Ilya Levental, Alina Kulakowska and
Paul A. Janmey
[Abstract]
Thermal Adaptation of Heat Shock Proteins
A. Muga and F. Moro
[Abstract]
Relaxin and Nitric Oxide Signalling
M.C. Baccari and D. Bani
[Abstract]
The Importance of Being Flexible: The Case of Basic Region
Leucine Zipper Transcriptional Regulators
Maria Miller
[Abstract]
The Endocannabinoid System: A Promising Target
for the Management of Type 2 Diabetes
André J. Scheen
[Abstract]
Angiotensin II in Type 2 Diabetes Mellitus
Kwan Yi Chu and Po Sing Leung
[Abstract]
Aminoacid Support in the Prevention of Diabetes and Diabetic
Complications
Carani Venkataraman Anuradha
[Abstract]
The Role of Islet Neogeneis-Associated Protein (INGAP)
in Pancreatic Islet Neogenesis
Gary L. Pittenger, David Taylor-Fishwick,
Aaron I. Vinik
[Abstract]
Incretin-Based Therapy of Type 2 Diabetes Mellitus
Filip K. Knop, Tina Vilsbøll
and Jens J. Holst
[Abstract]
Role of Resistin in Insulin Sensitivity in Rodents and
Humans
K.M. Barnes and J.L. Miner
[Abstract]
The Roles of the PDZ-containing Proteins Bridge-1 and PDZD2
in the Regulation of Insulin Production and Pancreatic Beta-Cell
Mass
Melissa K. Thomas, Siu Wai Tsang, Man-Lung
Yeung, Po Sing Leung and Kwok-Ming Yao
[Abstract]
Heat Shock Proteins in Diabetes and Wound Healing
Mustafa Atalay, Niku Oksala,
Jani Lappalainen, David E. Laaksonen, Chandan K.
Sen and Sashwati Roy
[Abstract]
Connexins, Diabetes and the Metabolic Syndrome
Romain Hamelin, Florent Allagnat,
Jacques - Antoine Haefliger and Paolo
Meda
[Abstract]
Ghrelin and Metabolic Disorders
Olavi Ukkola
[Abstract]
Perturbation Waves in Proteins and Protein Networks:
Applications of Percolation and Game Theories in Signaling
and Drug Design
Miklós A. Antal, Csaba Böde and Peter
Csermely
[Abstract]
Ligand-Receptor Communication and Drug Design
Pier G. De Benedetti and Francesca Fanelli
[Abstract]
Computational Modeling of Intramolecular and Intermolecular
Communication in GPCRs
Francesca Fanelli, Pier G. De Benedetti, Francesco Raimondi
and Michele Seeber
[Abstract]
Protein Domains as Information Processing Units
Tom Lenaerts, Joost Schymkowitz and Frederic Rousseau
[Abstract]
Allosteric Coupling and Conformational Fluctuations in Proteins
H.O. Onaran and T. Costa
[Abstract]
Intra and Inter-Molecular Communications Through
Protein Structure Network
Saraswathi Vishveshwara, Amit Ghosh and Priti Hansia
[Abstract]
Frameworks for Understanding Long-Range Intra-Protein
Communication
M.J. Whitley and A.L. Lee
[Abstract]
Allosteric Transitions in Biological Nanomachines
are Described by Robust Normal Modes of Elastic Networks
Wenjun Zheng, Bernard R. Brooks and D Thirumalai
[Abstract]
Abstracts
[Back to top]
The Retinal cGMP Phosphodiesterase γ-Subunit
— A Chameleon
Lian-Wang Guo and Arnold E. Ruoho
Intrinsically disordered proteins (IDPs) represent an emerging
class of proteins (or domains) that are characterized by a
lack of ordered secondary and tertiary structure. This group
of proteins has recently attracted tremendous interest primarily
because of a unique feature: they can bind to different targets
due to their structural plasticity, and thus fulfill diverse
functions. The inhibitory γ-subunit
(PDE?) of retinal PDE6 is an intriguing IDP, of which unique
protein properties are being uncovered. PDEγ
critically regulates the turn on as well as the turn off of
visual signaling through alternate interactions with the PDE6
catalytic core, transducin, and the regulator of G protein
signaling RGS9-1. The intrinsic disorder of PDEγ
does not compromise, but rather, optimizes its functionality.
PDEγ“curls
up” when free in solution but “stretches out”
when binding with the PDE6 catalytic core. Conformational
changes of PDEγ
also likely occur in its C-terminal PDE6-binding region upon
interacting with transducin during PDE6 activation. Growing
evidence shows that PDEγ
is also a player in non-phototransduction pathways, suggesting
additional protein targets. Thus, PDEγ
is highly likely to be adaptive in its structure and function,
hence a “chameleon”.
[Back to top]
Into the Lipid Realm: Stability and Thermodynamics
of Membrane Proteins
Francisco N. Barrera, Luis A. Alcaraz, Estefanía
Hurtado-Gómez and José L. Neira,
The first comprehensive studies on the structure and
thermodynamics of membrane proteins have started revealing
the exact architecture of these macromolecules and the physical-chemical
rules behind their structures. In this review, the stabilities
of several families of membrane proteins, obtained by using
spectroscopic, calorimetric and single molecule techniques
are surveyed. The data on the stability of membrane proteins
are compared with those obtained in soluble proteins. The
comparison indicates that although the number of particular
atomic interactions is larger in membrane proteins than in
soluble ones, the overall values are similar. The consensus
is that some intrinsic properties of membrane proteins resemble
those of soluble ones, but there are critical differences
arising form the inter-molecular contacts with the surrounding
membrane. Taken together, all these efforts improve our understanding
of the universal forces governing protein folding, and will
help in the design of membrane proteins in the near future.
[Back to top]
Advances and Pitfalls in Protein Structure Prediction
D. Cozzetto and A. Tramontano
Three dimensional protein structures are crucial for understanding
biology at both molecular and system level. Despite the advances
in experimental structural biology, the pace of sequence deposition
into databanks considerably exceeds that of structure determination.
Inevitably the functional annotation of genes and genomes
requires the exploitation of bioinformatics methods for protein
sequence comparison and structure prediction. Hence monitoring
objectively the state of art of the field is of paramount
importance, in order to make best use of computational protein
models to address biological questions. This review describes
some relevant issues in the field of structural bioinformatics,
emphasizig both open basic questions and the progress being
continuously achieved. It is reasonably expected that these
bioinformatics methods will increasingly contribute to the
biomedical, pharmaceutical and biotechnological research.
[Back to top]
Flexible Structures and Ligand Interactions of Tandem
Repeats Consisting of Proline, Glycine, Asparagine, Serine,
and/or Threonine Rich Oligopeptides in Proteins
Norio Matsushima, Hitoshi Yoshida, Yasuhiro Kumaki,
Masakatsu Kamiya, Takanori Tanaka, Yoshinobu Izumi and Robert
H. Kretsinger
Tandem repeats occur in 14% of all proteins. The repeat
unit lengths range from a single amino acid to more than 100
residues and the repeat number is sometimes over 100. Understanding
the structures, functions, and evolution of these repeats
is a significant goal in both proteomics and genomics. This
review summarizes experimental studies addressing structural
features of tandem repeats of short oligopeptides that are
rich in proline, glycine, asparagine, serine, and/or threonine.
The oligopetides include (PGMG) and (PNN) in biomineralization
protein (PM27), and (NPNA) in Plasmodium falciparum
circumsporozoite protein, (YSPTSPS) in RNA polymerase II,
(PHGGGWGQ) in the prion protein, (YGHGGG(N)) and (YNHGGG(G))
in plant glycine-rich proteins, (PGQGQQ), (PGQGQQGQQ) and
(GYYPTSOQQ) of wheat HMW glutenin, (FGGMGGGKGG) in Aequipecten
abductin. Spectroscopic studies including NMR and CD indicate
that these peptides adopt type I and II β-turns,
polyproline II helices, loop conformations, and random coils.
Formation of these structures frequently depends on pH, solvent,
temperature and hydration. The loop conformations are sometimes
stabilized by cation-π,
CH-π,
and/or amino-aromatic interactions. These observations indicate
that many tandem repeats are largely flexible. In addition
to generating repeating domains and providing flexible linkers
between domains, the tandem repeats of (PHGGGWGQ), (YGHGGG(N))
and (YNHGGG(G)) and those in titin bind Cu2+
ions; whereas, tandem repeats of (NPNA) and those in elastin
bind Ca2+ ions. The interactions
of some tandem repeats with various target proteins probably
involve an induced fit. The tandem repeats in tropoelastin,
flagelliform silk, wheat HMW glutenin, abductin, titin, and
human nucleoporin, nup153, are responsible for elastomeric
properties.
[Back to top]
Plasma Gelsolin: Function, Prognostic Value, and Potential
Therapeutic Use
Robert Bucki, Ilya Levental, Alina Kulakowska and
Paul A. Janmey
Gelsolin is a highly conserved, multifunctional
actin-binding protein initially described in the cytosol of
macrophages and subsequently identified in many vertebrate
cells. A unique property of gelsolin is that in addition to
its widely recognized function as a cytoplasmic regulator
of actin organization, the same gene expresses a splice variant
coding for a distinct isoform, plasma gelsolin, which is secreted
into extracellular fluids. The secreted form of gelsolin has
been implicated in a number of processes such as the extracellular
actin scavenging system and the presentation of lysophosphatidic
acid and other inflammatory mediators to their receptors,
in addition to its function as a substrate for extracellular
matrix-modulating enzymes. Consistent with these proposed
functions, blood gelsolin levels decrease markedly in a variety
of clinical conditions such as acute respiratory distress
syndrome, sepsis, major trauma, prolonged hyperoxia, malaria,
and liver injury. This correlation between blood gelsolin
levels and critical clinical conditions suggests the potential
utility of gelsolin as a prognostic marker as well as the
possibility for therapeutic replenishment of gelsolin to alleviate
the injurious cascades in these settings. This review summarizes
current data supporting a role of plasma gelsolin in extracellular
fluids and the potential for its use as a diagnostic marker
or therapeutic treatment in several medical conditions.
[Back to top]
Thermal Adaptation of Heat Shock Proteins
A. Muga and F. Moro
Heat shock proteins (Hsps) are molecular chaperones
that oppose stress-induced denaturation of other proteins.
Hsps are present in all organisms. Apart from assisting in
the efficient folding of newly synthesized proteins they maintain
pre-existing proteins in a stable conformation, preventing
their aggregation, under stress conditions. The latter role,
essential for thermal adaptation, requires that the chaperone
system change from a folding to a storing function at heat
shock temperatures. The temperature at which this change occurs
depends on the presence of a thermosensor in at least one
of the components of the chaperone systems. In this review,
we focus on the bacterial GroE and DnaK systems, describe
their temperature-sensitive protein components, and the location
of the thermosensor within the structure of these components.
While the thermosensor of the GroE system is located at the
inter-ring interface of GroEL, that of the DnaK system occurs
in its co-chaperone GrpE. Analysis of these examples demonstrates
the amazing mechanistic diversity of thermal stress adaptation
and of functional convergence of structurally unrelated proteins.
[Back to top]
Relaxin and Nitric Oxide Signalling
M.C. Baccari and D. Bani
The peptide hormone relaxin (RLX) has been
shown to exert a variety of functions in both reproductive
and non-reproductive tissues. The molecular mechanism of RLX
on its target cells appears to involve multiple intracellular
signalling systems, including the nitric oxide (NO) pathway.
NO is an ubiquitous molecule synthesised from L-arginine under
the catalytic action of different nitric oxide synthase (NOS)
isoforms and its altered production has been reported to be
involved in several diseases. RLX has been demonstrated to
promote NO biosynthesis by up-regulating NOS expression; its
influence on the different NOS appears to depend on the cell
type studied. In addition to its physiological roles, RLX
has been postulated as a potential therapeutic agent in several
diseases. In particular, based on its property to promote
NO biosynthesis, RLX may be regarded as a therapeutic tool
in diseases characterized pathogenically by an impaired NO
production. The aim of the present mini-review is to summarize
and discuss the pathophysiological actions of RLX, strictly
related to its ability to activate the endogenous NO pathway
in reproductive and non-reproductive target organs.
[Back to top]
The Importance of Being Flexible: The Case of
Basic Region Leucine Zipper Transcriptional Regulators
Maria Miller
Large volumes of protein sequence and structure
data acquired by proteomic studies led to the development
of computational bioinformatic techniques that made possible
the functional annotation and structural characterization
of proteins based on their primary structure. It has become
evident from genome-wide analyses that many proteins in eukaryotic
cells are either completely disordered or contain long unstructured
regions that are crucial for their biological functions. The
content of disorder increases with evolution indicating a
possibly important role of disorder in the regulation of cellular
systems. Transcription factors are no exception and several
proteins of this class have recently been characterized as
premolten/molten globules. Yet, mammalian cells rely on these
proteins to control expression of their 30,000 or so genes.
Basic region:leucine zipper (bZIP) DNA-binding proteins constitute
a major class of eukaryotic transcriptional regulators. This
review discusses how conformational flexibility “built”
into the amino acid sequence allows bZIP proteins to interact
with a large number of diverse molecular partners and to accomplish
their manifold cellular tasks in a strictly regulated and
coordinated manner.
[Back to top]
The Endocannabinoid System: A Promising
Target for the Management of Type 2 Diabetes
André J. Scheen
Type 2 diabetes is closely related to abdominal obesity
and is generally associated with other cardiometabolic risk
factors, resulting in a high incidence of cardiovascular complications.
Several animal and human observations suggest that the endocannabinoid
(EC) system is overactivated in presence of abdominal obesity
and/or diabetes, and contributes to disturbances of energy
balance and metabolism. Not only it regulates the intake of
nutrients through central mechanisms located within the hypothalamus
and limbic area, but it also intervenes in transport, metabolism
and deposit of the nutrients in the digestive tract, liver,
adipose tissue, skeletal muscle, and possibly pancreas. Activation
of both central and peripheral CB1 receptors promotes weight
gain and associated metabolic changes. Conversely, rimonabant,
the first selective CB1 receptor antagonist in clinical use,
has been shown to reduce body weight, waist circumference,
triglycerides, blood pressure, insulin resistance and C-reactive
protein levels, and to increase HDL cholesterol and adiponectin
concentrations in both non-diabetic and diabetic overweight/obese
patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin
(HbA1c) levels was observed in metformin- or sulfonylurea-treated
patients with type 2 diabetes and in drug-naïve diabetic
patients. Almost half of metabolic changes occurred beyond
weight loss, in agreement with direct peripheral effects.
Rimonabant was generally well-tolerated, but with a slightly
higher incidence of depressed mood disorders, anxiety, nausea
and dizziness compared to placebo. New trials are supposed
to confirm the potential role of rimonabant (and other CB1
neutral antagonists or inverse agonists) in overweight/obese
patients with type 2 diabetes and high risk cardiovascular
disease.
[Back to top]
Angiotensin II in Type 2 Diabetes Mellitus
Kwan Yi Chu and Po Sing Leung
Angiotensin II (Ang II) is well-known as a systemic
vasoconstrictor but recently a novel role for the peptide
in endocrine function has been suggested and it has been linked
to the pathophysiology of type 2 diabetes mellitus. According
to several large-scale clinical studies, blocking Ang II prevented
the onset of type 2 diabetes in potential patients. Type 2
diabetes is a complicated disease that is primarily characterized
by insulin resistance and relative insulin deficiency mediated
by numerous organs. Among these organs, the pancreas, adipose
tissue, skeletal muscle and liver are the most prominent in
maintaining glucose homeostasis. Interestingly, locally generated
Ang II has been identified in these organs, where it plays
different physiological roles and is produced in relatively
high amounts with significant function. In type 2 diabetic
human patients or animal models, Ang II, its generating enzymes
and receptors are up-regulated and trigger detrimental effects.
Moreover, Ang II seems to play roles in the regulation of
insulin secretion by the pancreatic ß-cell and insulin
sensitivity by peripheral tissues, which are two critical
factors contributing to the development of type 2 diabetes.
Accordingly, inhibiting Ang II produced beneficial effects
on individual organs and throughout the body. Therefore, the
present review discusses the role of Ang II in particular
organs during normal physiological conditions as well as in
type 2 diabetes.
[Back to top]
Aminoacid Support in the Prevention of Diabetes and Diabetic
Complications
Carani Venkataraman Anuradha
Emerging evidence suggests that amino acids may be potentially
important in the prevention of diabetes and diabetes-associated
complications. The pathways involved in the pathogenesis of
diabetic complications include increased polyol pathway flux,
increased advanced glycation end products formation, activation
of protein kinase C and oxidative and carbonyl stress. This
review will discuss the modulatory effects of amino acids
on insulin secretion and their action in concert with insulin
as signaling molecules. Evidences for the role of some amino
acids in controlling glycemia and glucose-triggered pathological
pathways are also included. Individual amino acids, especially
the ones bestowed with antioxidant property like N-acetyl
cysteine and taurine seem to have beneficial effects by their
ability to reduce intracellular oxidative stress generation
and glycooxidation. Other amino acids like glycine and lysine
may be good candidates for the prevention of glycation. Nutritional
intervention with taurine, phenyl alanine or branched chain
amino acids can improve insulin sensitivity and post-prandial
glucose disposal. Deficiency of one or more amino acids has
been observed in diabetes and the beneficial effects of amino
acids in some studies are positively correlated with the increase
in plasma levels of these amino acids. Inclusion of individual
amino acids/mixture, perhaps as a combinational therapy with
conventional treatment protocols could be of therapeutic interest.
[Back to top]
The Role of Islet Neogeneis-Associated Protein (INGAP)
in Pancreatic Islet Neogenesis
Gary L. Pittenger, David Taylor-Fishwick,
Aaron I. Vinik
Efforts to cure diabetes are now focused on restoring
a physiologically-regulated population of insulin-producing
cells to the patient. A number of animal models of β
cell regeneration have been employed to study the mechanisms
of the process. Islet neogenesis, the regeneration of pancreatic
islets from pancreatic stem cells, is arguably the least fraught
with barriers to widespread use as a therapy for diabetes.
These animal models have led to the description of the reg
family of proteins that appear to be related to islet regeneration.
Islet neogenesis-associated protein (INGAP) is an initiator
of islet neogenesis in animal models and a peptide sequence
from INGAP carries the biological activity. INGAP peptide
has been shown to stimulate an increase in ? cell mass in
mice, rats, hamsters and dogs. INGAP is also found in the
pancreas in human pathological states involving islet neogenesis.
The peptide has been tested in human clinical trials, with
success being reported. The evidence points to INGAP as a
major factor in stimulating islet neogenesis, and, therefore,
may play a significant therapeutic role in diabetes.
[Back to top]
Incretin-Based Therapy of Type 2 Diabetes Mellitus
Filip K. Knop, Tina Vilsbøll and Jens
J. Holst
This review article focuses on the therapeutic potential
of the incretin hormones, glucagon-like peptide-1 (GLP-1)
and glucose-dependent insulinotropic polypeptide (GIP), in
treating type 2 diabetes mellitus (T2DM). T2DM is characterized
by insulin resistance, impaired glucose-induced insulin secretion
and inappropriately regulated glucagon secretion which in
combination eventually result in hyperglycemia and in the
longer term microvascular and macrovascular diabetic complications.
Traditional treatment modalities - even multidrug approaches
- for T2DM are often unsatisfactory at getting patients to
glycemic goals as the disease progresses due to a steady,
relentless decline in pancreatic beta-cell function. Furthermore,
current treatment modalities are often limited by inconvenient
dosing regimens, safety and tolerability issues, the latter
including hypoglycemia, body weight gain, edema and gastrointestinal
side effects. Therefore, the actions of GLP-1 and GIP, which
include potentation of meal-induced insulin secretion and
trophic effects on the beta-cell, have attracted a lot of
interest. GLP-1 also inhibits glucagon secretion, and suppresses
food intake and appetite. Two new drug classes based on the
actions of the incretin hormones have recently been approved
for therapy of T2DM; injectable long-acting stable analogues
of GLP-1, incretin mimetics, and orally available
inhibitors of dipeptidyl peptidase 4 (DPP4; the enzyme responsible
for the rapid degradation of GLP-1 and GIP), the so-called
incretin enhancers. This review article focuses on
these two new classes of antidiabetic agents and will outline
the scientific basis for the development of incretin mimetics
and incretin enhancers, review clinical experience gathered
so far and discuss future expectations for incretin-based
therapy.
[Back to top]
Role of Resistin in Insulin Sensitivity in Rodents and
Humans
K.M. Barnes and J.L. Miner
Resistin is a potential link between obesity and insulin resistance
or type 2 diabetes. In rodents, resistin is primarily expressed
in and secreted from mature adipocytes, with some expression
in pancreatic islets and portions of the pituitary and hypothalamus.
Its secretion can be up-regulated by several factors, including
insulin and glucose. The exposure of rodents, or their cells,
to resistin results in decreased response to insulin. This
is likely in part due to an up-regulation of suppressor of
cytokine signaling (SOCS)-3, which interferes with the activation
of insulin receptor substrate (IRS)-1. However, in humans
resistin is expressed primarily by macrophages and seems to
be involved in the recruitment of other immune cells and the
secretion of pro-inflammatory factors, including tumor necrosis
factor (TNF)α. Human resistin may interfere with insulin
signaling by stimulating the expression of phosphatase and
tensin homolog deleted on chromosome ten (PTEN), which dephosphorylates
3-phosphorylated phosphoinositide (PIP3). Resistin
also seems to be involved in the development of atherosclerosis
in humans by promoting the formation of foam cells and the
proliferation and migration of vascular endothelial and smooth
muscle cells. Many of the inflammatory related functions of
human resistin appear to be regulated by activation of the
nuclear factor (NF)kB transcription factor. The divergent
roles of resistin in humans and rodents are evident by the
data presented in this review but they will not be able to
be fully understood until the resistin receptor is identified.
[Back to top]
The Roles of the PDZ-containing Proteins Bridge-1
and PDZD2 in the Regulation of Insulin Production and Pancreatic
Beta-Cell Mass
Melissa K. Thomas, Siu Wai Tsang,
Man-Lung Yeung, Po Sing Leung and Kwok-Ming Yao
PDZ domains are versatile protein interaction modules
with the ability to dimerize and to recognize internal and
carboxy-terminal peptide motifs. Their function in mediating
the formation of multi-molecular signaling complexes is best
understood at neuronal and epithelial membranes. In a screen
for interactors that regulate transcription factor function
in pancreatic beta cells, we isolated two PDZ-containing proteins
Bridge-1 (PSMD9) and PDZD2, which contain one and six PDZ
domains, respectively. Here, we review their functions in
the regulation of pancreatic beta cells as a nuclear coactivator
or extracellular signaling molecule. Bridge-1 interacts with
both E12 and PDX-1 to stimulate insulin promoter activity.
Recent gain-of-function analysis in both cell and transgenic
models has revealed its functions to regulate both insulin
gene expression and pancreatic beta-cell survival. Little
is known about the intracellular function of PDZD2 that is
predominantly localized to the endoplasmic reticulum of INS-1E
cells. Interestingly, PDZD2 is proteolytically processed by
caspase-3 to generate a carboxy-terminal secreted protein
(sPDZD2) containing two PDZ domains. Expressed in fetal pancreatic
progenitor and INS-1E cells, sPDZD2 when added as recombinant
protein exerts concentration-dependent mitogenic effects on
beta-like cells. We propose that the PDZ domain proteins Bridge-1
and PDZD2 likely transduce signals that regulate insulin production,
proliferation, and survival of pancreatic beta cells.
[Back to top]
Heat Shock Proteins in Diabetes and Wound Healing
Mustafa Atalay, Niku Oksala, Jani
Lappalainen, David E. Laaksonen, Chandan K. Sen
and Sashwati Roy
The heat shock proteins (HSPs), originally identified as heat-inducible
gene products, are a highly conserved family of proteins that
respond to a wide variety of stress. Although HSPs are among
the most abundant intracellular proteins, they are expressed
at low levels under normal physiological conditions, and show
marked induction in response to various stressors. HSPs function
primarily as molecular chaperones, facilitating the folding
of other cellular proteins, preventing protein aggregation,
or targeting improperly folded proteins to specific pathways
for degradation. By modulating inflammation, wound debris
clearance, cell proliferation, migration and collagen synthesis,
HSPs are essential for normal wound healing of the skin. In
this review, our goal is to discuss the role and clinical
implications of HSP with respect to skin wound healing and
diabetes. The numerous defects in the function of HSPs associated
with diabetes could contribute to the commonly observed complications
and delayed wound healing in diabetics. Several physical,
pharmacological and genetic approaches may be considered to
address HSP-directed therapies both in the laboratory and
in the clinics.
[Back to top]
Connexins, Diabetes and the Metabolic Syndrome
Romain Hamelin, Florent Allagnat2,
Jacques - Antoine Haefliger and Paolo
Meda
Diabetes and the related metabolic syndrome are multi
system disorders that result from improper interactions between
various cell types. Even though the underlying mechanism remains
to be fully understood, it is most likely that both the long
and the short distance range cell interactions, which normally
ensure the physiologic functioning of the pancreas, and its
relationships with the insulin-targeted organs, are altered.
This review focuses on the short-range type of interactions
that depend on the contact between adjacent cells and, specifically,
on the interactions that are dependent on connexins. The widespread
distribution of these membrane proteins, their multiple modes
of action, and their interactions with conditions/molecules
associated to both the pathogenesis and the treatment of the
2 main forms of diabetes and the metabolic syndrome, make
connexins an essential part of the chain of events that leads
to metabolic diseases. Here, we review the present state of
knowledge about the molecular and cell biology of the connexin
genes and proteins, their general mechanisms of action, the
roles specific connexin species play in the endocrine pancreas
and the major insulin-targeted organs, under physiological
and patho-physiological conditions.
[Back to top]
Ghrelin and Metabolic Disorders
Olavi Ukkola
Ghrelin is a gut-brain peptide that has somatotropic,
food intake increasing and adipogenic effects. Ghrelin is
involved in modulating insulin and glucose metabolism in rodents
according to recent studies. In humans acylated ghrelin reduces
insulin sensitivity while unacylated ghrelin has opposite
effects. In general, ghrelin seems to have diabetogenic effects.
Obese, in particular abdominally obese, subjects have low
ghrelin levels and decreased total ghrelin levels have been
associated with metabolic syndrome and Type 2 diabetes. Most
of the human studies in Type 1 diabetes have reported low
ghrelin levels probably as a compensatory mechanism against
hyperglycaemia. The data on obestatin in the regulation of
energy balance is extremely contradictory. Interestingly,
ghrelin receptor antagonists may improve glucose tolerance
in rats without inducing weight gain by increasing insulin
secretion. Antagonism of ghrelin function to treat type 2
diabetes is thus a fascinating idea. This review concentrates
on recent findings on the orexigenic peptide ghrelin and its
derivatives in metabolic disorders with emphasis put on human
studies.
[Back to top]
Perturbation Waves in Proteins and Protein Networks:
Applications of Percolation and Game Theories in Signaling
and Drug Design
Miklós A. Antal, Csaba Böde and Peter
Csermely
The network paradigm is increasingly used to describe
the dynamics of complex systems. Here we review the current
results and propose future development areas in the assessment
of perturbation waves, i.e. propagating structural changes
in amino acid networks building individual protein molecules
and in protein-protein interaction networks (interactomes).
We assess the possibilities and critically review the initial
attempts for the application of game theory to the often rather
complicated process, when two protein molecules approach each
other, mutually adjust their conformations via multiple communication
steps and finally, bind to each other. We also summarize available
data on the application of percolation theory for the prediction
of amino acid network- and interactome-dynamics. Furthermore,
we give an overview of the dissection of signals and noise
in the cellular context of various perturbations. Finally,
we propose possible applications of the reviewed methodologies
in drug design.
[Back to top]
Ligand-Receptor Communication and Drug Design
Pier G. De Benedetti and Francesca Fanelli
Ligand-protein and protein-protein interactions play
a pivotal role in any cellular process and function by means
of complex and dynamic mechanisms that involve sophisticated
intra- and intermolecular communication pathways.
The deeper understanding of the molecular and structural mechanisms
of these pathways of chemical information transfer constitutes
the foundations of rational druggable target discovery and
drug design. In this context the role of both molecular recognition/communication
between the interacting partners and their quantitative/dynamic
description constitute the crucial point.
In this respect, many approaches at different level of complexity
have been developed and applied to different druggable target
like enzymes, membrane receptors and protein assembly. They
mainly differ in the accuracy and resolution level of molecular
description and, hence, in the derived quantitative molecular
descriptors/predictors and ligand-target models.
In this review, we will try to illustrate some selected examples
of ligand-target receptor protein models, by comparatively
considering both series of ligands (ligand-based communication
modeling) and ligand-target complexes ( target-based communication
modeling) in order to describe the relevant structural/dynamic
features of chemical information transfer in the ligand/drug
design endeavour.
[Back to top]
Computational Modeling of Intramolecular and Intermolecular
Communication in GPCRs
Francesca Fanelli, Pier G. De Benedetti, Francesco Raimondi
and Michele Seeber
Intramolecular and intermolecular communication is a
privileged issue in G protein-Coupled Receptor (GPCR) function
as the prominent role of these receptors is to respond to
extracellular signals by catalyzing nucleotide exchange in
intracellular G proteins.
In the last decade or so we have applied much effort in elaborating
computational strategies to infer the mechanisms of intramolecular
and intermolecular communication in a number of GPCRs of the
rhodopsin family. In this article, we review the most relevant
achievements on the matter.
In summary, the receptor sites of activating mutations or
ligand-binding communicate with a common allosteric site in
the cytosolic domains. This was inferred from the observation
that local perturbations by activating mutations or ligands
correlate with increases in solvent accessibility of the neighborhoods
of the highly conserved E/DRY receptor motif. The latter turned
out to be the primary recognition point for the C-terminus
of the G protein α-subunit,
independent of the receptor or the G protein type.
In spite of the highly composite nature of the receptor-G
protein interface, receptor contacts with the C-terminus of
the α5-helix
seem to be the major players in the receptor-catalyzed formation
of a nucleotide exit route. The latter would lie in between
the αF-helix
and the β6/α5
loop, which detach from each other upon receptor binding,
giving solvent accessibility to the nucleotide.
A worthy inference of the studies is that GPCRs employ common
pathways for the transfer of functionally relevant information.
[Back to top]
Protein Domains as Information Processing Units
Tom Lenaerts, Joost Schymkowitz and Frederic Rousseau
Transducing environmental signals from the cell surface to
the nucleus in order to evoke appropriate gene regulatory
response requires an accurate and robust medium to propagate
biological information. The structure of proteins and especially
the dynamic properties of these structures allows for the
uptake and restitution of biological information from and
to the environment. To understand the functioning and regulation
of signalling pathways we therefore have to understand how
protein structures encode biological information. Towards
this goal several computational methods have been carried
out over the last years. First we will provide an overview
of these in silico approaches. Next, using the well known
SH2 domain as a case study, we describe two specific approaches
in more detail to illustrate the similarities and differences
between sequence-based and structure-based methods for the
analysis of protein communication. Both methods address the
same question yet from a different level of description. As
a consequence both have their limits and a number of pros
and cons that are discussed here. Together all the methods
discussed here provide an arsenal of in silico approaches
that may be used to understand how information content is
maintained through protein structural dynamics, elucidating
explicitly information transfer in signalling networks.
[Back to top]
Allosteric Coupling and Conformational Fluctuations in
Proteins
H.O. Onaran and T. Costa
Proteins in their native folded states can possess
multiple energy minima and they can show constant conformational
fluctuations at physiological temperatures. In this article,
we discuss the quantitative relationship between ligand-induced
perturbation of such fluctuations, modeled as probability
distributions of conformational substates, and allosteric
coupling of ligand binding to different sites, as defined
by linkage thermodynamics. We show that allosteric coupling
between two binding events on the same protein is an inevitable
consequence of ligand-induced perturbations of the probability
distribution that represents conformational fluctuations in
thermal equilibrium. When high resolution structural data
of a protein in empty and ligand-bound forms are available,
the COREX algorithm can provide, in principle, an excellent
bridge between the energetics of substates distribution in
the protein ensemble and structural coordinates. Here we propose
a COREX-based strategic approach to link structural perturbations
and the free energy changes of allosteric coupling. This strategy
might be broadly useful in the endeavor of predicting how
specific ligands allosterically regulate the function of specific
proteins.
[Back to top]
Intra and Inter-Molecular Communications Through Protein
Structure Network
Saraswathi Vishveshwara, Amit Ghosh and Priti Hansia
Communication within and across proteins is crucial for
the biological functioning of proteins. Experiments such as
mutational studies on proteins provide important information
on the amino acids, which are crucial for their function.
However, the protein structures are complex and it is unlikely
that the entire responsibility of the function rests on only
a few amino acids. A large fraction of the protein is expected
to participate in its function at some level or other. Thus,
it is relevant to consider the protein structures as a completely
connected network and then deduce the properties, which are
related to the global network features. In this direction,
our laboratory has been engaged in representing the protein
structure as a network of non-covalent connections and we
have investigated a variety of problems in structural biology,
such as the identification of functional and folding clusters,
determinants of quaternary association and characterization
of the network properties of protein structures. We have also
addressed a few important issues related to protein dynamics,
such as the process of oligomerization in multimers, mechanism
of protein folding, and ligand induced communications (allosteric
effect). In this review we highlight some of the investigations
which we have carried out in the recent past.
A review on protein structure graphs was presented earlier,
in which the focus was on the graphs and graph spectral properties
and their implementation in the study of protein structure
graphs/networks (PSN). In this article, we briefly summarize
the relevant parts of the methodology and the focus is on
the advancement brought out in the understanding of protein
structure-function relationships through structure networks.
The investigations of structural/biological problems are divided
into two parts, in which the first part deals with the analysis
of PSNs based on static structures obtained from x-ray crystallography.
The second part highlights the changes in the network, associated
with biological functions, which are deduced from the network
analysis on the structures obtained from molecular dynamics
simulations.
[Back to top]
Frameworks for Understanding Long-Range Intra-Protein
Communication
M.J. Whitley and A.L. Lee
The phenomenon of intra-protein communication is
fundamental to such processes as allostery and signaling,
yet comparatively little is understood about its physical
origins despite notable progress in recent years. This review
introduces contemporary but distinct frameworks for understanding
intra-protein communication by presenting both the ideas behind
them and a discussion of their successes and shortcomings.
The first framework holds that intra-protein communication
is accomplished by the sequential mechanical linkage of residues
spanning a gap between distal sites. According to the second
framework, proteins are best viewed as ensembles of distinct
structural microstates, the dynamical and thermodynamic properties
of which contribute to the experimentally observable macroscale
properties. Nuclear magnetic resonance (NMR) spectroscopy
is a powerful method for studying intra-protein communication,
and the insights into both frameworks it provides are presented
through a discussion of numerous examples from the literature.
Distinct from mechanical and thermodynamic considerations
of intra-protein communication are recently applied graph
and network theoretic analyses. These computational methods
reduce complex three dimensional protein architectures to
simple maps comprised of nodes (residues) connected by edges
(inter-residue “interactions”). Analysis of these
graphs yields a characterization of the protein’s topology
and network characteristics. These methods have shown proteins
to be “small world” networks with moderately high
local residue connectivities existing concurrently with a
small but significant number of long range connectivities.
However, experimental studies of the tantalizing idea that
these putative long range interaction pathways facilitate
one or several macroscopic protein characteristics are unfortunately
lacking at present. This review concludes by comparing and
contrasting the presented frameworks and methodologies for
studying intra-protein communication and suggests a manner
in which they can be brought to bear simultaneously to further
enhance our understanding of this important fundamental phenomenon.
[Back to top]
Allosteric Transitions in Biological Nanomachines
are Described by Robust Normal Modes of Elastic Networks
Wenjun Zheng, Bernard R. Brooks and D Thirumalai
Allostery forms the basis of intra-molecular communications
in various enzymes, however the underlying conformational
changes are largely elusive. Recently, we have proposed to
employ an elastic model based normal mode analysis to investigate
the allosteric transitions in several molecular nanomachines
(including myosin II, DNA polymerase and chaperonin GroEL).
After combining with bioinformatics analysis of the evolutionary
sequence variations, we have been able to identify the highly
conserved and robust modes of collective motions that are
capable of transmitting molecular signals over long distances.
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