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Current Protein & Peptide
Science
ISSN: 1389-2042
Current Protein and Peptide
Science
Volume 8, Number 5, October 2007
Contents
Chaperonin GroEL: Structure and Reaction Cycle
Pp. 418-425
K. Ananda Krishna, G. Venkateswara Rao and K.R.S. Sambasiva
Rao
[Abstract]
Movement of Endosymbiotic Organelles Pp.
426-438
Serena Schmidt von Braun and Enrico Schleiff
[Abstract]
Development of a Protease Production Platform for
Structure Based Drug Design Pp. 439-445
Ted Fox, Debra Brennan, Douglas A. Austen, Susanne E.
Swalley, Joyce T. Coll, Scott A. Raybuck and Stephen P. Chambers
[Abstract]
A Review of Defensins of Diverse Origins
Pp. 446-459
Jack H. Wong, Lixin Xia and T.B. Ng
[Abstract]
Role of Cooperativity in Protein Folding and Protein
Mosaic Assemblage Relevance for Protein Conformational Diseases
Pp. 460-470
L.F. Agnati, D. Guidolin, G. Leo, S. Genedani, P. Århem,
A. Forni, N. Andreoli and K. Fuxe
[Abstract]
A Role of the 9-Aminoacridines and their Conjugates
in a Life Science Pp. 471-483
Jaroslav ebestík, Jan Hlavá ek and Ivan
Stibor
[Abstract]
“Forbidden” Disulfides: Their Role as
Redox Switches Pp. 484-495
M.A. Wouters, R.A. George and N.L. Haworth
[Abstract]
Functional Regulation of Hepatic Cytochrome P450 Enzymes
by Physicochemical Properties of Phospholipids in Biological
Membranes Pp. 496-505
Taeho Ahn, Mihee Kim, Chul-Ho Yun and Han-Jung Chae
[Abstract]
Antimicrobial Peptides in Burns and Wounds
Pp. 506-520
Satyanarayan Bhat and Stephen Milner
[Abstract]
Abstracts
[Back to top]
Chaperonin GroEL: Structure and Reaction
Cycle
K. Ananda Krishna, G. Venkateswara Rao and K.R.S. Sambasiva
Rao
The structure of Escherichia coli chaperonin GroEL
was studied using various experimental tools. Such studies
produced information about its structure with increasing details.
Moreover, remarkable advances in experimental methods provided
a step forward in understanding the reaction cycle involved
in GroEL-mediated protein folding. In the current review we
summarize recent progress, focus on the structure of GroEL
and understand the mechanism involved in GroEL-mediated protein
folding. This review is divided into the following sections:
(i) Section 1 provides basic understanding on protein folding,
(ii) Section 2 not only describes various tools used to elucidate
the structural aspects of GroEL but also provides details
about its structure with particular emphasis, (iii) Section
3 describes allosteric transitions and the reaction cycle
involved in GroEL-mediated protein folding, (iv) Section 4
explains iterative annealing and smoothing of the energy landscape
model and finally (v) Section 5 discusses applications and
recent progress.
[Back to top]
Movement of Endosymbiotic Organelles
Serena Schmidt von Braun and Enrico Schleiff
Mitochondria and chloroplasts are both of endosymbiotic origin.
Upon symbiosis the ancestral bacteria had to be incorporated
into the regulatory cellular network. A long known phenomenon
is thereby the alteration of the positioning of the organelles
in response to extra- and intracellular stimuli. For chloroplasts,
the repositioning is a response to light intensity changes
in order to optimize the photosynthetic process. Mitochondria
movement ensures a positioning of the organelle close to the
place where its function is required, e.g. in metabolic pathways,
apoptosis, regulation of cytosolic calcium levels and ATP
production. Even though the morphological description of the
movement was circumstantiated decades ago, only recent research
gave some insights into the molecular concepts behind the
movement of organelles and its regulation. Mitochondrial movement
is influenced for instance by calcium but also by small molecules
like lysophos-phatidic acid or metals like zinc. In turn,
chloroplasts move in response to light. The light quality
giving the impulse for movement depends on the plants investigated.
As for mitochondria, calcium is an important second messenger
for that process. The organelle movement is achieved by actin
or tubulin. The recent discovery of proteins involved in the
modulation of the movement like milton and miro in mitochondria
or phot1 and phot2 and the organelle localized protein chup1,
possibly facilitating the cytoskeleton contact, marked a new
area of understanding of the process. This review will focus
on a comprehensive overview on recent discoveries of the regulatory
components.
[Back to top]
Development of a Protease Production Platform for
Structure Based Drug Design
Ted Fox, Debra Brennan, Douglas A. Austen, Susanne E.
Swalley, Joyce T. Coll, Scott A. Raybuck and Stephen P. Chambers
Structure-based drug design (SBDD) has played an integral
role in the development of highly specific, potent protease
inhibitors resulting in a number of drugs in clinical trials
and on the market. Possessing biochemical assays and structural
information on both the target protease and homologous family
members helps ensure compound selectivity. We have redesigned
the path from clone to protein eliminating many of the traditional
bottlenecks associated with protein production to ensure a
constant supply to feed many diverse protease drug discovery
programs. The process was initiated with the design of a multi-system
vector, capable of expression in both eukaryotic and prokaryotic
hosts; this vector also facilitated high-throughput cloning,
expression and purification. When combined into an expression
screen, supplemented with salvage screens for detergent extraction
and refolding, a route for protein production was established
rapidly. Using this process-orientated approach we have successfully
expressed and purified all mechanistic classes of active human
and viral proteases for enzymatic assays and crystallization
studies. While exploiting recent developments in high-throughput
biochemistry, we still employ classical biophysical techniques
such as light-scattering and analytical ultracentrifugation,
to ensure the highest quality protein enters crystallization
trials. We have drawn on examples from our own research programs
to illustrate how these strategies have been successfully
used in the production of proteases for SBDD.
[Back to top]
A Review of Defensins of Diverse Origins
Jack H. Wong, Lixin Xia and T.B. Ng
Defensins are a family of peptides with potent antimicrobial
activity. They are found in various organisms. The intent
of this article is to review the structures and mechanisms
of antimicrobial actions of defensins produced by different
organisms including humans, other mammals, birds, reptiles,
fish, mollusks, arthropods, plants and fungi. The evolution
and possible applications of these defensins are discussed.
[Back to top]
Role of Cooperativity in Protein Folding and Protein
Mosaic Assemblage Relevance for Protein Conformational Diseases
L.F. Agnati, D. Guidolin, G. Leo, S. Genedani, P. Århem,
A. Forni, N. Andreoli and K. Fuxe
Biological systems are organized in intricate and highly structured
networks with hierarchies and multiple scales. Cells can be
considered as “meso-scale level” systems placed
between the “macro-scale level” (systems of cellular
networks) and the “micro-scale level” (systems
of molecular networks). In fact, cells represent complex biochemical
machineries made by networks of molecules connected by biochemical
reactions. Thus, the brain should be studied as a system of
“networks of networks”. Recently, the existence
of a Global Molecular Network (GMN) enmeshing the entire CNS
was proposed. This proposal is based on the evidence that
the extra-cellular matrix is a dynamic molecular structure
capable of storing and releasing signals and of interacting
with receptors and proteins on the cell membranes. Proteins
have a special role in molecular networks since they can be
assembled into high-order molecular complexes, which have
been defined as Protein Mosaics (PM). Protein monomers in
a PM (the “tesserae” of the mosaic) can interact
via classical and non-classical cooperativity behaviour involving
allosteric interactions.
In the present paper, new features of allostery and cooperativity
for protein folding, assemblage and topological features of
PM will be discussed. Against this background, alterations
in PM via allosteric modulations and non-classical cooperativity
mechanisms may lead to protein aggregates like beta amyloid
fibrils. Such aggregates cause pathological changes in the
GMN structure and function leading to neurodegenerative diseases
such as Alzheimer’s disease. Thus, a novel view of the
so called Protein Conformational Diseases (PCD) is proposed.
[Back to top]
A Role of the 9-Aminoacridines and their Conjugates
in a Life Science
Jaroslav ebestík, Jan Hlavá ek and Ivan
Stibor
The 9-aminoacridines play an important role in medicine. They
were applied first in a treatment of protozoal infections
in the beginning of the last century. Recently, it has been
shown that the 9-aminoacridines are successful candidates
for treatment of cancer, viral and prion diseases. Their conjugation
with biomolecules such as peptides and proteins may modulate
their activity, bioavailability and applicability. This review
deals with the synthesis of 9-aminoacridine, its conjugation
with variety of molecules and utilization of such conjugates
in several fields of science.
[Back to top]
“Forbidden” Disulfides: Their Role as
Redox Switches
M.A. Wouters, R.A. George and N.L. Haworth
Seminal studies by Richardson [1] and Thornton [2] defined
the constraints imposed by protein structure on disulfide
formation and flagged forbidden regions of primary or secondary
structure seemingly incapable of forming disulfide bonds between
resident cysteine pairs. With respect to secondary structure,
disulfide bonds were not found between cysteine pairs:
A. on adjacent β-stands
[1];
B. in a single helix or strand [2];
C. on non-adjacent strands of the same β-sheet
[2].
In primary structure, disulfide bonds were not found between
cysteine pairs:
D. adjacent in the sequence [2].
In the intervening years it has become apparent that all these
forbidden regions are indeed occupied by disulfide-bonded
cysteines, albeit rather strained ones. It has been observed
that sources of strain in a protein structure, such as residues
in forbidden regions of the Ramachandran plot and cis-peptide
bonds, are found in functionally important regions of the
protein and warrant further investigation [3-5]. Like the
Ramachandran plot, the earlier studies by Richardson [1] and
Thornton [2] have identified a fundamental truth in protein
stereochemistry: “forbidden” disulfides adopt
strained conformations, but there is likely a functional reason
for this. Emerging evidence supports a role for forbidden
disulfides in redox-regulation of proteins.
[Back to top]
Functional Regulation of Hepatic Cytochrome P450 Enzymes
by Physicochemical Properties of Phospholipids in Biological
Membranes
Taeho Ahn, Mihee Kim, Chul-Ho Yun and Han-Jung Chae
Knowledge regarding the regulation of hepatic cytochrome P450
(P450) is crucial to the fields of drug therapy and drug development,
as well as to our understanding of the mechanisms underlying
the metabolic activation of toxic and carcinogenic compounds.
P450 is a membrane-anchored protein that shows a variety of
interaction with membrane phospholipids, which affect the
membrane topology and catalytic activities of the protein.
In particular, anionic phospholipids, nonbilayer forming lipids,
and the degree of saturation of the lipid fatty acyl chain
play important roles in the functional regulation of P450,
as well as in the bilayer structure of the membrane. However,
despite the importance of phospholipids in the regulation
of P450s, the interaction of the protein with membrane phospholipids,
and the membrane properties induced by phospholipids which
regulate P450, are unclear. In this review, we describe the
effect of the physicochemical properties of the phospholipid
constituents of biological membranes on hepatic P450 catalytic
activity, membrane insertion (and/or penetration), and structural
changes.
[Back to top]
Antimicrobial Peptides in Burns and Wounds
Satyanarayan Bhat and Stephen Milner
Burn-induced immunosuppression not only increases susceptibility
to infection, but also predisposes burn patients to related
adverse sequelae, including systemic inflammatory response
syndrome and sepsis. Although burn-related immunosuppression
is not fully understood, it is characterized by decreased
T- and B-lymphocyte function and by impaired functions of
circulating leukocytes and complement. Alterations in defensins,
a family of cationic, naturally occurring antimicrobial peptides,
may underlie these immune deficiency patterns. Defensins are
considered important components of the innate immune system,
as they inhibit bacterial, fungal, and viral colonization.
They also chemoattract immature dendritic cells and T lymphocytes,
recruit neutrophils, macrophages, and monocytes, modulate
complement and adjuvant activity, and promote inflammation
and wound healing. Infectious states are associated with upregulation
of circulating defensins, which suggests an underlying antimicrobial
role. In addition, data from our laboratory demonstrated diminished
levels of certain defensins in burned tissue. The inference
is that decreased defensin levels in burn injury may facilitate
infection and subsequent sepsis. It may also alter functions
of T- and B-lymphocytes, neutrophils, macrophages, and complement,
thereby contributing to the pathophysiology of burn-related
systemic inflammatory responses. This article is a comprehensive
review on the role of antimicrobial peptides in burns and
wounds.
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