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Current
Protein & Peptide Science
ISSN:1389-2042
Current Protein and Peptide
Science
Volume 6, Number 5, October 2005
Contents
Biomedicine & Bioinformatics
Guest Editor: Kuo-Chen Chou
Editorial Pp.397
NMR Studies on How the Binding Complex of Polyisoprenol
Recognition Sequence Peptides and Polyisoprenols Can Modulate
Membrane Structure Pp.399
Guo-Ping Zhou and Frederic A. Troy
[Abstract]
HIV-1 gp120 V3 Loop for Structure-Based Drug
Design Pp.413
Suzanne Sirois, Tobias Sing and Kuo-Chen Chou
[Abstract]
Progress in Protein Structural Class Prediction
and its Impact to Bioinformatics and Proteomics Pp.423
Kuo-Chen Chou
[Abstract]
Analysis of the Phosphoryl Transfer Mechanism of c-AMP
dependent Protein Kinase (PKA) by Penta-Coodinate Phosphoric
Transition State Theory Pp.437
Feng Nia, Wu Lib, Yan-Mei Lib and Yu-Fen Zhaoa
[Abstract]
Computational Methods for Protein-Protein Interaction
and their Application Pp.443
Tie-Liu Shi, Yi-Xue Li, Yu-Dong Cai and Kuo-Chen
Chou
[Abstract]
Anesthetics as Chemical Tools to Study the Structure
and Function of Nicotinic Acetylcholine Receptors
Pp.451
Hugo R. Arias and Pankaj Bhumireddy
[Abstract]
Anesthetics as Chemical Tools to Study the Structure
and Function of Nicotinic Acetylcholine Receptors Pp.473
Hugo R. Arias and Pankaj Bhumireddy
[Abstract]
Pattern Recognition Methods for Protein Functional
Site Prediction Pp.479
Zheng Rong Yang,, Lipo Wang, Natasha Young, Dave
Trudgian and Kuo-Chen Chou
[Abstract]
Abstracts
[Back to top]
Editorial
We are now living in a period of human genome just being
completed and entering the post-genomic era that concentrates
on harvesting the fruits hidden in the genomic text. One of
the important signs from the pre-genomic to the post-genomic
era is the emergence of a new scientific branch called “bioinformatics”,
and its penetration into biomedicine, among many other areas.
The goal of biomedicine is to apply biological and physiological
principles to clinical practice, while that of bioinformatics
is to provide computer-based methods for coping with and interpreting
the genomic data that are being uncovered in large volumes
within the diverse genome sequencing projects and other new
experimental technology in molecular biology. Actually, the
two branches have been stimulating and penetrating each other
ever since the generation of bioinformatics. On one hand,
some long-standing and fundamental problems in biomedicine
have challenged and stimulated the development of many powerful
tools in bioinformatics; but on the other hand, the progress
in bioinformatics has empowered it to deal with many complicated
objects so as to timely open new research avenues and encourage
novel stretegies for conducting various in-depth studies in
biomedicine, significantly enriching its contents. The current
thematic issue is focused on the two areas, particularly their
mutual penetration and stimulation.
A problem of fundamental importance in glycobiology is how
membrane-bound hydrophilic glycoconjugates are translocated
across hydrophobic membranes. The review entitled “NMR
Studies on How the Binding Complex of Polyisoprenol Recognition
Sequence Peptides and Polyisoprenols Can Modulate Membrane
Structure” by Dr. Guo-Ping Zhou (Senior Research Fellow,
Beth Israel Deaconess Medical Center, Harvard Medical School)
and Dr. Frederic A. Troy II (Professor of Biochemistry and
Molecular Medicine, University of California School of Medicine
at Davis) was written to address the unresolved problem of
how sugar chains attached to the polyisoprenol (PI) glycosyl
carrier lipids, dolichylphosphate and undecapreylphosphate,
are ferried across cell membranes. It reviews a combination
of 1H- and 31P NMR spectroscopy and energy minimized molecular
modeling studies that revealed the preferred orientation of
PIs in model phospholipids membranes. It also reviews how
membrane proteins containing a PI recognition sequences (PIRS)
uses this motif to mediate their binding to the PIs. Evidence
supporting the hypothesis that a PI:PIRS binding complex may
have the potential of forming a membrane channel that could
potentially facilitate glycoconjugate translocation is reviewed
as well.
HIV-1 gp120 V3 loop sequences and their associated co-receptors
CCR5 and CXCR4 form the basis for structure-based drug design.
In the review by Dr. Suzanne Sirois (Adjunct Professor at
the Chemistry Department of the Université du Québec
à Montréal; Member of the Immuno Deficiency
Treatment Center at the Montreal General Hospital, McGill
University), Mr. Tobias Sing (Ph.D. candidate with Max-Planck-Institut
für Informatik, Germany), and Professor Kuo-Chen Chou,
it is summarized that the molecular modeling studies have
provided useful insights into the potential mechanisms of
co-receptor CCR5 usage and the development of small molecule
inhibitors. Moreover, the role of the host immunophilin cyclophilin
A (CypA) in the protein-protein interaction between gp120-V3
loop and CCR5 is reviewed.
With the avalanche of new protein sequences we are facing
in the post-genomic era, it is highly desired to develop an
automated method for fast and accurately determining the protein
attributes (such as subcellular localization, enzyme class,
and type associated with membrane) for a newly-found protein
sequence that are closely related to its biological functions.
In the review entitled “Progress in Protein Structural
Class Prediction and Its Impact to Bioinformatics and Proteomics”
by Dr. Kuo-Chen Chou, the progress in protein structural class
prediction and how it has penetrated into the other areas
and stimulated their development have been discussed.
The review by Feng Ni (Ph.D. candidate), Wu Li (Postdoctoral
associate), Yan-Mei Li (Professor ), and Yu-Fen Zhao (Professor
of Chemistry Department, Tsinghua University, Beijing; Member
of Chinese Academy of Sciences) introduces the recent progress
in the research of phosphoryl transfer mechanism of PKA (C-AMP
dependent protein kinase). By combining a series of relevant
experimental and theoretical calculation results, a novel
phosphoryl transfer mechanism in PKA was proposed. Since many
ATP-binding enzymes may share the similar phosphoryl transfer
mechanism, it might also be used to interpret the mechanisms
of these enzymes, such as molecular motor and phosphatase.
The paper by Tie-Liu Shi (Associate Professor and Deputy
Director of Bioinformation Center of SIBS, Chinese Academy
of Sciences), Yi-Xue Li (Professor and Director of Bioinformation
Center of SIBS, Chinese Academy of Sciences), Yu-Dong Cai
(Specially Appointed Professor of Bioinformation Center of
SIBS, Chinese Academy of Sciences; Research Scientist of Gordon
Life Science Institute) and Prof. Dr. Kuo-Chen Chou, has summarized
a series of the current bioinformatics methods for predicting
protein-protein interactions, as well as their applications
to the relevant areas. The coverage and limitation of these
methods have also been discussed.
The review contributed by Dr. Hugo R. Arias (Assistant Professor
with Department of Pharmaceutical Sciences, College of Pharmacy,
Western University of Health Sciences in California) and Mr.
Pankaj Bhumireddy (MA candidate) is to introduce the progress
on the topic that local and general anesthetics can be used
to better understand and characterize the structure of nicotinic
receptors.
In spite of their diverse tissue architectures and biological
mandates, the immunological and neuronal systems exert quite
comparable tasks. The paper by Biao Wang (Postdoctoral Fellow),
Na Zhang, Kai-Xian Qian, and Jian-Guo Geng (Assistant Professor,
University of Minnesota Medical School) is focused on the
above phenomena. It is illustrated in their review that the
immune cells and the neurons are apparently under the control
of rather conserved mechanisms at the molecular levels, implying
that immunologists and neurobiologists will learn, share and
benefit greatly from each other for the knowledge, experience
and expertise common to these two seemingly divergent fields.
Finally, the paper by Zheng Rong Yang (Reader of Department
of Computer Science, University of Exeter, UK), Lipo Wang
(Associate Professor, School of Electrical and Electronic
Engineering, Nanyang Technological University, Singapore),
Natasha Young (Research Student), and Professor Kuo-Chen Chou,
reviews the progresses in applying various pattern recognition
methods to the prediction of protein functional sites.
As one can see from the review papers covered in this issue,
the inter-penetration between biomedicine and bioinformatics
is an inexorable trend, particularly in the the post-genomic
era.
Kuo-Chen Chou, Ph.D. D.Sc.
Chief Scientist of Gordon Life Science Institute
13784 Torrey Del Mar Drive
San Diego, CA 92130,
USA
March 28, 2005
[Back to top]
NMR Studies on How the Binding Complex of Polyisoprenol
Recognition Sequence Peptides and Polyisoprenols Can Modulate
Membrane Structure
Guo-Ping Zhou and Frederic A. Troy
The glycosyl carrier lipids, dolichylphosphate (C95-P)
and undecapreylphosphate (C55-P) are key molecular
players in the synthesis and translocation of complex glycoconjugates
across cell membranes. The molecular mechanism of how these
processes occur remains a mystery. Failure to completely catalyze
C95-P-mediated N-linked protein glycosylation is
lethal, as are defects in the C55-P-mediated synthesis
of bacterial cell surface polymers. Our recent NMR studies
have sought to understand the role these “super-lipids”
play in biosynthetic and translocation pathways, which are
of critical importance to problems in human biology and molecular
medicine. The PIs can alter membrane structure by inducing
in the lamellar phospholipids (PL) bilayer a non-lamellar
or hexagonal (HexII) structure. Membrane proteins
that bind PIs contain a transmembrane binding motif, designated
a PI recognition sequence (PIRS). Herein we review our recent
combination of 1H- and 31P NMR spectroscopy
and energy minimized molecular modeling studies that have
determined the preferred orientation of PIs in model phospholipids
membranes. They also show that the addition of a PIRS peptide
to nonlamellar membranes induced by the PIs can reverse the
HexII phase back to a lamellar structure. Our molecular
modeling calculations have also shown that as many as five
PIRS peptides can bind to a single PI molecule. These findings
lead to the hypothesis that the PI-induced HexII structure
may have the potential of forming a membrane chan-nel that
could facilitate glycoconjugate translocation processes. This
is an alternate hypothesis to the possible existence of hypothetical
“flippases” to accomplish movement of hydrophilic
sugar chains across hydrophobic membranes.
[Back to top]
HIV-1 gp120 V3 Loop for Structure-Based Drug Design
Suzanne Sirois, Tobias Sing and Kuo-Chen Chou
HIV-1 cell entry is mediated by sequential interactions
of the envelope protein gp120 with the receptor CD4 and a
coreceptor, usually CCR5 or CXCR4, depending on the individual
virion. Considerable efforts on exploiting the HIV coreceptors
as drug targets have led to the new class of coreceptor antagonists.
While these antiretroviral drugs aim at preventing virus/coreceptor
interaction by binding to host proteins, neutralizing antibodies
directed against the core-ceptor-binding sites on gp120 have
attracted attention as possible vaccine candidates. However,
both approaches are complicated by the multiple protective
mechanisms of gp120 which allow for rapid escape from selective
pressures ex-erted by drugs or antibodies. Thus, advances
in rational drug and vaccine design rely heavily on improved
insights into the relation between genotype and phenotype,
the evolution of coreceptor usage, and, ultimately the structural
biology of coreceptor usage and inhibition. The third variable
(V3) loop of gp120, crucially involved in all these aspects,
will be a major focus of this review.
[Back to top]
Progress in Protein Structural Class Prediction and
its Impact to Bioinformatics and Proteomics
Kuo-Chen Chou
The structural class is an important attribute used to characterize
the overall folding type of a protein or its domain. Since
the concept of protein structural class was developed about
3 decades ago based on a visual inspection of polypeptide
chain topologies in a dataset of only 31 gloular proteins,
the number of structure-known proteins has been increased
rapidly. For example, as of 12-July-2005, the entries deposited
into RCSB PDB Protein Data Bank for proteins, peptides, and
viruses whose 3-dimensional structures were determined by
X-ray and NMR techniques have been increased to 28,920. To
properly cover more and more structure-known proteins, some
modification and expansion from the original structural classification
scheme have been developed. Meanwhile, many different approaches
have been proposed for predicting the structural class of
proteins. In this review, the new classification schemes are
briefly introduced. The attention is focused on the progress
in structural class prediction and its impact in stimulating
the development of identifying the other attributes of proteins.
It is interesting to point out that the development of the
latter has actually in turn greatly enriched the power of
the former. Also, some promising approaches for the further
development of protein structural class prediction are also
addressed.
[Back to top]
Analysis of the Phosphoryl Transfer Mechanism of c-AMP
dependent Protein Kinase (PKA) by Penta-Coodinate Phosphoric
Transition State Theory
Feng Nia, Wu Lib, Yan-Mei Lib and Yu-Fen Zhaoa
This review briefly covers recent literature of research
on the phosphoryl transfer mechanism of PKA. Combining experimental
and theoretical calculation results on enzymes with experimentally
observed biomimic activities of phosphoryl amino acids and
a small molecular model of catalytic core in PKA, a novel
mechanism was proposed. The cooperative participation roles
of both Asp166 and Lys168 via a penta-coodinate phosphoric
intermediate was elucidated to conciliate the current different
views of the phosphoryl transfer mechanism of PKA. Since many
ATP-binding enzymes may share a similar phosphoryl transfer
mechanism, this proposed mechanism might also apply to the
mechanism of these enzymes, e.g., molecular motor and phosphatase
among others.
[Back to top]
Computational Methods for Protein-Protein Interaction
and their Appli-cation
Tie-Liu Shi, Yi-Xue Li, Yu-Dong Cai and Kuo-Chen Chou
Protein-protein interactions play a central role in numerous
processes in cell and are one of the main research fields
in current functional proteomics. The increase of finished
genomic sequences has greatly stimulated the progress for
detecting the functions of the genes and their encoded proteins.
As complementary ways to the high through-put ex-perimental
methods, various methods of bioinformatics have been developed
for the study of the protein-protein interac-tion. These methods
range from the sequence homology-based to the genomic-context
based. Recently, it tends to inte-grate the data from different
methods to build the protein-protein interaction network,
and to predict the protein function from the analysis of the
network structure. Efforts are ongoing to improve these methods
and to search for novel aspects in genomes that could be exploited
for function prediction. This review highlights the recent
advances of the bioinfor-matics methods in protein-protein
interaction researches. In the end, the application of the
protein-protein interaction has also been discussed.
[Back to top]
Anesthetics as Chemical Tools to Study the Structure
and Function of Nicotinic Acetylcholine Receptors
Hugo R. Arias and Pankaj Bhumireddy
The nicotinic acetylcholine receptor (AChR) is the archetype
of the Cys-loop ligand-gated ion channel receptor superfamily.
Noncompetitive antagonists inhibit the AChR without interacting
directly with agonist sites. Among noncompetitive antagonists,
general and local anesthetics have been used for decades to
study the structure and function of muscle- as well as neuronal-type
AChRs. In this review, we address and update all information
regarding the charac-terization of binding sites and the mechanism
of action for n-alkanols, barbiturates, inhalational and dissociative
general anesthetics, as well as for tertiary and quaternary
local anesthetics. The experimental evidence outlined in this
review suggest that: (1) several neuronal-type
AChRs might be targets for the pharmacological action of distinct
anesthetics; (2) the molecular components
of a specific anesthetic locus on a certain receptor type
are different from the structural de-terminants of the site
for the same anesthetic on a different receptor type; (3)
there are unique binding sites for distinct anesthetics in
the same receptor; (4) the affinity of a
specific anesthetic depends on the AChR conformational state;
(5) anesthetics may inhibit AChRs by different
mechanisms including open-channel-blocking, augmenting the
desensitization process, and/or inactivating the opening of
resting receptors; and (6) some anesthetics
may potentiate AChR activity.
[Back to top]
Conserved Molecular Players for Axon Guidance and
Angiogenesis
Biao Wang, Na Zhang, Kai-Xian Qian and Jian-Guo Geng
Neuronal guidance cues attract or repel axons and/or neurons
and play important roles in the pathfinding of neuronal networks
and the functioning of nervous system. Prominent among them
are the families of ephrins, semaphorins, Slits and netrins
and their cognate cell-surface receptors. Due to their biological
significance, extensive research has been carried out in the
last ten years or so. Angiogenesis is a cellular process of
capillary sprouting and configuring of neovasculatures, which
shares many developmental, anatomical, physiological and pathophysiological
features with the neural counterparts. This review will summarize
the emerging evidence indicating the common molecular mechanisms
underlying both axon guidance (including neuronal migration)
and angiogenesis for exquisite regulation of proper wiring
of both systems.
[Back to top]
Pattern Recognition Methods for Protein Functional
Site Prediction
Zheng Rong Yang, Lipo Wang, Natasha Young1, Dave Trudgian
and Kuo-Chen Chou
Protein functional site prediction is closely related to
drug design, hence to public health. In order to save the
cost and the time spent on identifying the functional sites
in sequenced proteins in biology laboratory, computer programs
have been widely used for decades. Many of them are implemented
using the state-of-the-art pattern recognition algorithms,
including decision trees, neural networks and support vector
machines. Although the success of this effort has been obvious,
advanced and new algorithms are still under development for
addressing some difficult issues. This review will go through
the major stages in developing pattern recognition algorithms
for protein functional site prediction and outline the future
research directions in this important area.
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