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Current
Protein & Peptide Science
ISSN: 1389-2037
Current Protein and Peptide
Science
Volume 9, Number 3, June 2008
Contents
Coupling Caspase Cleavage and Proteasomal Degradation
of Proteins Carrying PEST Motif Pp. 210-220
José E. Belizario, Juliano Alves, Miguel Garay-Malpartida
and João Marcelo Occhiucci
[Abstract]
Extracellular SH3 Domain Containing Proteins –
Features of a New Protein Family Pp. 221-226
R. Stoll and A. Bosserhoff
[Abstract]
Natural Compounds with Proteasome Inhibitory Activity
for Cancer Prevention and Treatment 227-239
H. Yang, K.R. Landis-Piwowar, D. Chen, V. Milacic
and Q.P. Dou
[Abstract]
Drug-Like Inhibitors of Protein-Protein Interactions:
A Structural Examination of Effective Protein Mimicry
Pp. 240-247
D.C. Fry
[Abstract]
Recent Advances in QSAR and Their Applications
in Predicting the Activities of Chemical Molecules, Peptides
and Proteins for Drug Designb Pp. 248-259
Qi-Shi Du, Ri-Bo Huang and Kuo-Chen Chou
[Abstract]
Search Strategies in Structural Bioinformatics
Pp. 260-274
Mark T. Oakley, Daniel Barthel, Yuri Bykov, Jonathan
M. Garibaldi, Edmund K. Burke, Natalio Krasnogor and Jonathan
D. Hirst
[Abstract]
Research Advances of Endostatin and its Short
Internal Fragments Pp. 275-283
Huan-Li Xu, Hai-Ning Tan, Feng-Shan Wang and
Wei Tang
[Abstract]
Inactivation of Indispensable Bacterial Proteins
by Early Protein of Bacteriophages: Implication in Antibacterial
Drug Discovery Pp. 284-290
S. Sau, P. Chattoraj, T. Ganguly, P.K. Chanda
and N.C. Mandal
[Abstract]
Natural Protective Amyloidsb Pp. 291-309
Vassiliki A. Iconomidou and Stavros J. Hamodrakas
[Abstract]
Abstracts
[Back to top]
Coupling Caspase Cleavage and Proteasomal Degradation
of Proteins Carrying PEST Motif
José E. Belizario, Juliano Alves, Miguel Garay-Malpartida
and João Marcelo Occhiucci
The degradation is critical to activation and deactivation
of regulatory proteins involved in signaling pathways to cell
growth, differentiation, stress responses and physiological
cell death. Proteins carry domains and sequence motifs that
function as prerequisite for their proteolysis by either individual
proteases or the 26S multicomplex proteasomes. Two models
for entry of substrates into the proteasomes have been considered.
In one model, it is proposed that the ubiquitin chain attached
to the protein serves as recognition element to drag them
into the 19S regulatory particle, which promotes the unfolding
required to its access into the 20S catalytic chamber. In
second model, it is proposed that an unstructured tail located
at amino or carboxyl terminus directly track proteins into
the 26S/20S proteasomes. Caspases are cysteinyl aspartate
proteases that control diverse signaling pathways, promoting
the cleavage at one or two sites of hundreds of structural
and regulatory protein substrates. Caspase cleavage sites
are commonly found within PEST motifs, which are segments
rich in proline (P), glutamic acid (D), aspartic acid (E)
and serine (S) or threonine (T) residues. Considering that
N- and C- terminal peptide carrying PEST motifs form disordered
loops in the globular proteins after caspase cleavage, it
is postulated here that these exposed termini serve as unstructured
initiation site, coupling caspase cleavage and ubiquitinproteasome
dependent and independent degradation of short-lived proteins.
This could explain the inherent susceptibility to proteolysis
among proteins containing PEST motif.
[Back to top]
Extracellular SH3 Domain Containing Proteins –
Features of a New Protein Family
R. Stoll and A. Bosserhoff
In the year 1994, the protein MIA (melanoma inhibitory
activity) was found to be strongly expressed and secreted
by malignant melanomas and subsequent studies revealed that
MIA has an important function in melanoma development and
invasion. Multidimensional NMR-spectroscopy and x-ray crystallography
revealed that recombinant human MIA adopts a Src homology
3 (SH3) domain-like fold in solution, a structure with two
perpendicular antiparallel three and five-stranded beta-sheets.
SH3 domains are protein modules that are found in many intracellular
signalling proteins and mediate protein-protein interactions
by binding to proline-rich peptide sequences. Unlike previously
described protein structures with SH3 domain folds, MIA is
a secreted single-domain protein of 12 kDa that contains an
additional antiparallel beta-sheet and two disulfide bonds.
Furthermore, the charge surrounding the canonical binding
site differs from that of classical SH3 domains. The two disulfide
bonds are crucial for correct folding and function as revealed
by mutation analysis. Therefore, MIA appears to be the first
extracellular protein adopting an SH3 domain-like fold. MIA
was shown to interact with fibronectin, and MIA-interacting
peptide ligands identified by phage display screening are
similar to the consensus sequence of type III human fibronectin
repeats, especially FN14. Interestingly, recent data revealed
that MIA can also directly bind to integrin alpha 4 beta 1
and alpha 5 beta1 and that it modulates integrin activity
negatively. These findings suggest an interesting role of
the SH3-domain proteins in the extracellular compartment.
Recently, MIA homologous proteins with a sequence identity
of 44% and a sequence homology of approximately 80% were determined
(TANGO, MIA-2, OTOR). This clearly suggests that this structural
device is used more frequently, in processes ranging from
developmental changes to the interference of cell attachment
in the extracellular matrix. Detailed studies are necessary
to determine the exact function of the MIA homologous proteins.
It will be interesting to know whether additional protein
families can be identified which are secreted and carry SH3
domain-like modules, in addition to elucidate what the specific
physiological targets of this protein family are.
[Back to top]
Natural Compounds with Proteasome Inhibitory Activity
for Cancer Prevention and Treatment
H. Yang, K.R. Landis-Piwowar, D. Chen, V. Milacic
and Q.P. Dou
The proteasome is a multicatalytic protease complex that
degrades most endogenous proteins including misfolded or damaged
proteins to ensure normal cellular function. The ubiquitin-proteasome
degradation pathway plays an essential role in multiple cellular
processes, including cell cycle progression, proliferation,
apoptosis and angiogenesis. It has been shown that human cancer
cells are more sensitive to proteasome inhibition than normal
cells, indicating that a proteasome inhibitor could be used
as a novel anticancer drug. Indeed, this idea has been supported
by the encouraging results of the clinical trials using the
proteasome inhibitor Bortezomib (Velcade, PS-341), a drug
approved by the US Food and Drug Administration (FDA). Several
natural compounds, including the microbial metabolite lactacystin,
green tea polyphenols, and traditional medicinal triterpenes,
have been shown to be potent proteasome inhibitors. These
findings suggest the potential use of natural proteasome inhibitors
as not only chemopreventive and chemotherapeutic agents, but
also tumor sensitizers to conventional radiotherapy and chemotherapy.
In this review, we will summarize the structures and biological
activities of the proteasome and several natural compounds
with proteasome inhibitory activity, and will discuss the
potential use of these compounds for the prevention and treatment
of human cancers.
[Back to top]
Drug-Like Inhibitors of Protein-Protein Interactions:
A Structural Examination of Effective Protein Mimicry
D.C. Fry
Protein-protein interactions represent targets for drug
discovery that are highly relevant in a biological sense,
but have proven difficult in a practical sense. Nevertheless,
there have been recent successes in discovering drug-like
small molecule inhibitors of protein-protein systems. To build
on this progress, it is worth analyzing successful cases to
understand at a molecular level the strategies by which these
compounds effectively interfere with protein-protein pairing.
A commonly observed situation is one wherein the small molecule
acts as a direct mimic of one of the protein partners. This
review focuses exclusively on cases where this strategy is
employed, and examines the structural characteristics of the
binding sites and the conformational attributes of the small
molecule ligands. Common traits shared among these successful
examples are identified, and formulated into potentially useful
guidance for drug discovery efforts within this target class.
[Back to top]
Recent Advances in QSAR and Their Applications in
Predicting the Activities of Chemical Molecules, Peptides
and Proteins for Drug Design
Qi-Shi Du, Ri-Bo Huang and Kuo-Chen Chou
This review is to summarize three new QSAR (quantitative
structure-activity relationship) methods recently developed
in our group and their applications for drug design. Based
on more solid theoretical models and advanced mathematical
techniques, the conventional QSAR technique has been recast
in the following three aspects. (1) In the fragment-based
two dimensional QSAR, or abbreviated as FB-QSAR, the molecular
structures in a family of drug candidates are divided into
several fragments according to the substitutes being investigated.
The bioactivities of drug candidates are correlated with physicochemical
properties of the molecular fragments through two sets of
coefficients: one is for the physicochemical properties and
the other for the molecular fragments. (2) In the multiple
field three dimensional QSAR, or MF-3D-QSAR, more molecular
potential fields are integrated into the comparative molecular
field analysis (CoMFA) through two sets of coefficients: one
is for the potential fields and the other for the Cartesian
three dimensional grid points. (3) In the AABPP (amino acid-based
peptide prediction), the bioactivities of peptides or proteins
are correlated with the physicochemical properties of all
or partial residues of the sequence through two sets of coefficients:
one is for the physicochemical properties of amino acids and
the other for the weight factors of the residues. Meanwhile,
an iterative double least square (IDLS) technique is developed
for solving the two sets of coefficients in a training dataset
alternately and iteratively. Using the two sets of coefficients,
one can predict the bioactivity of a query peptide, protein,
or drug candidate. Compared with the old methods, the new
QSAR approaches as summarized in this review possess machine
learning ability, can remarkably enhance the prediction power,
and provide more structural information. Meanwhile, the future
challenge and possible development in this area have been
briefly addressed as well.
[Back to top]
Search Strategies in Structural Bioinformatics
Mark T. Oakley, Daniel Barthel, Yuri Bykov, Jonathan
M. Garibaldi, Edmund K. Burke, Natalio Krasnogor and Jonathan
D. Hirst
Optimisation problems pervade structural bioinformatics.
In this review, we describe recent work addressing a selection
of bioinformatics challenges. We begin with a discussion of
research into protein structure comparison, and highlight
the utility of Kolmogorov complexity as a measure of structural
similarity. We then turn to research into de novo protein
structure prediction, in which structures are generated from
first principles. In this endeavour, there is a compromise
between the detail of the model and the extent to which the
conformational space of the protein can be sampled. We discuss
some developments in this area, including off-lattice structure
prediction using the great deluge algorithm. One strategy
to reduce the size of the search space is to restrict the
protein chain to sites on a regular lattice. In this context,
we highlight the use of memetic algorithms, which combine
genetic algorithms with local optimisation, to the study of
simple protein models on the two-dimensional square lattice
and the face-centred cubic lattice.
[Back to top]
Research Advances of Endostatin and its Short Internal
Fragments
Huan-Li Xu, Hai-Ning Tan, Feng-Shan Wang and
Wei Tang
Endostatin, the C-terminal fragment of collagen XVIII,
is a potent angiogenesis inhibitor. At present, there are
a large number of research papers on endostatin. However,
the action mechanism of endostatin is still a matter of ongoing
discussion. The objective of this review is to elucidate its
origin and elementary structure, and to discuss its structure
basis of activity and action mechanisms based on the latest
research. Furthermore, some published studies reporting the
antiangiogenic effects of endostatin-derived peptides were
also reviewed. It is proposed that the amino acid sequence
of endostatin contains both angiosuppressive and angiostimulatory
domains. Short endostatin fragments may be exploited as a
new angiogenesis inhibitor for therapeutic applications, in
substitution of the full length endostatin. These studies
on endostatin fragments also shed light on our understanding
of the molecular action mechanisms of endostatin.
[Back to top]
Inactivation of Indispensable Bacterial Proteins by
Early Protein of Bacteriophages: Implication in Antibacterial
Drug Discovery
S. Sau, P. Chattoraj, T. Ganguly, P.K. Chanda
and N.C. Mandal
Bacteriophages utilize host bacterial cellular machineries
for their own reproduction and completion of life cycles.
The early proteins that phage synthesize immediately after
the entry of their genomes into bacterial cells participate
in inhibiting host macromolecular biosynthesis, initiating
phage-specific replication and synthesizing late proteins.
Inhibition of synthesis of host macromolecules that eventually
leads to cell death is generally performed by the physical
and/or chemical modification of indispensable host proteins
by early proteins. Interestingly, most modified bacterial
proteins were shown to take part actively in phage-specific
transcription and replication. Research on phages in last
nine decades has demonstrated such lethal early proteins that
interact with or chemically modify indispensable host proteins.
Among the host proteins inhibited by lethal phage proteins,
several are not inhibited by any chemical inhibitor available
today. Under the context of widespread dissemination of antibiotic-resistant
strains of pathogenic bacteria in recent years, the information
of lethal phage proteins and cognate host proteins could be
extremely invaluable as they may lead to the identification
of novel antibacterial compounds. In this review, we summarize
the current knowledge about some early phage proteins, their
cognate host proteins and their mechanism of action and also
describe how the above interacting proteins had been exploited
in antibacterial drug discovery.
[Back to top]
Natural Protective Amyloids
Vassiliki A. Iconomidou and Stavros J. Hamodrakas
Amyloidoses are a group of diseases including neurodegenerative
diseases like Alzheimer’s disease and also type II diabetes,
spongiform encephalopathies and many others, believed to be
caused by protein aggregation and subsequent amyloid fibril
formation. However, occasionally, living organisms exploit
amyloid fibril formation, a property inherent into amino acid
sequences, and perform specific physiological functions from
amyloids, in differing biological contexts. Some of these
functional amyloids are natural protective amyloids. Here,
we review recent evidence on silkmoth chorion protein synthetic
peptide-analogues that documents the function of silkmoth
chorion, the major component of the eggshell, a structure
with extraordinary physiological and mechanical properties,
as a natural protective amyloid. Also, we briefly discuss
the reported function of other natural, protective amyloids
like fish chorion, the protein Pmel17 which forms amyloid
fibrils that act as templates and accelerate the covalent
polymerization of reactive small molecules into melanin, the
hydrophobins and the antifreeze protein from winter flounder.
Molecular self-assembly is becoming an increasingly popular
route to new supramolecular structures and molecular materials
and the inspiration for such structures is commonly derived
from self-assembling systems in biology. Therefore, a careful
examination of these studies may set the basis for the exploration
of new routes for the formation of novel biocompatible polymeric
structures with exceptional physico-chemical properties, for
potentially new biomedical and industrial applications.
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