|
Faculty
 Martin R. Schiller
Associate Professor of Molecular, Microbial, and Structural Biology
schiller@nso.uchc.edu
Areas of Interest:
Bioinformatics and Axonal outgrowth.
Short functional peptide motifs
Developing protein-protein interaction theory is important for our
understanding of the cell, disease mechanisms, and to facilitate drug
design. The theory behind protein-protein interactions is based on first
principle theory of molecular interactions and the identification of a
rapidly growing number of short peptide motifs (less than 15 amino
acids) that can bind to, or be acted upon by protein domains. Other than
those interactions mediated through short motifs we have virtually no
ability to predict protein-protein interactions. My lab is continuing
annotation of Minimotif Miner, the first bioinformatics tool that is a
comprehensive database of short functional motifs currently containing
~1000 unique motifs (Balla et al, 2006). Minimotif Miner can be used by
any scientist to generate new hypotheses about the function of any
protein and postulate mechanisms by which mutations cause any human
disease (Schiller, 2007). Current projects are aimed at completing this
database, enhancing the specificity of motif definitions and using
Minimotif miner to identify new drug targets in HIV.
Axonal Outgrowth
Another central focus of my laboratory is axonal outgrowth.
Understanding how neurons initiate axon outgrowth is important, not just
for our basic understanding of neuronal connectivity, but also for
treating neurodegenerative diseases, spinal cord injury, and head
trauma. Axonal outgrowth requires the coordination of many cellular
processes. As the axon navigates the nervous system to find targets, it
must make complicated decisions that require a higher level of
interpretation. Very little is known how the axon is capable of
interpreting the many inputs it receives. to address this question, we
are continuing to study how a multidomain protein called Kalirin is
involved in coordination of axonal signal processing (May et al., 2001;
Penzes et al., 2003; Schiller et al., 2005, Schiller et al., 2006,
Chakrabarti et al., 2006, Schiller, 2007)
Lab Rotation Projects:
Project A: Regulation of Kalirin’s GEF activity.
Understanding how neurons initiate neurite outgrowth is important, not
just for our basic understanding of development of the nervous system
and neuronal morphology, but also to aid in the development of therapies
for neurological disorders. The Kalirin guanine nucleotide exchange
factor (GEF) domain is important for inducing neuronal outgrowth in
large projection neurons. We first plan to investigate the regulation of
the GEF domain in the full-length Kalirin protein, use these studies to
screen for drugs that disrupt the GEF regulation, and screen drugs for
their ability to induce neuronal regeneration in rodent models. As a
first step toward this goal we have identified that the spectrin,
repeats, pleckstrin homology (PH) and Src homology 3 (SH3) domain(s)
regulate Kalirins GEF activity. We have identified that inter- and
intramolecular association of the SH3 domain is part of the mechanism
that controls GEF activity. The rotation project will begin to
investigate the mechanism by which the PH domain and phosphoinositides
control the GEF activity of Kalirin. The project will involve,
structural biology, cell biology and enzyme kinetics.
Project B: The receptor for nerve growth factor TrkA is a receptor
tyrosine kinase involved in neuronal survival and neurite outgrowth.
Our laboratory has identified that the pleckstrin homology domain of
Kalirin binds to the TrkA receptor and that this interaction is critical
for efficient activation of and signaling from the TrkA receptor. With
the long term goal of making drugs that activate this receptor tyrosine
kinase, our lab has projects to solve the structure of the Kalirin-PH
domain/TrkA complex by NMR spectroscopy, map the motif in TrkA that
binds Kalirin-PH1, or explore the specificity of this interaction.
Project C: Identification of novel short motifs in the C-termini
of proteins.
Homology analysis is one of the best approaches for identifying domains
and predicting gene function. In addition to domains, many short
minimotifs of less than 15 amino acids confer functions to proteins such
as posttranslation modification, protein-protein interaction, and
protein trafficking. While comprehensive databases and search interfaces
for analyzing protein domains exist, resources to search proteins for
minimotifs are of narrow scope, with most minimotif databases examining
a small subset of the known minimotifs. We have generated a Minimotif (MnM)
database containing 312 minimotifs and a web-based simple motif search (SMS)
system for identifying minimotifs in proteins. Statistical modeling of
complete proteomes and homology analysis are used to increase the
probability that the identified minimotifs are of biological function.
Using this approach we have also identified several hundred novel motifs
in the C-termini of proteins in the human proteome, which are conserved
in other proteomes. Many known C-terminal motifs (e.g PDZ motif) are
important for the functions of neuronal proteins. The rotation project
will identify proteins that bind to several of these novel C-terminal
motifs.
Laboratory Home Page
Publications
Selected Publications:
Machida K, Thompson CM, Dierck K, Jablonowski , K Karkkainen S, Liu
B, Zhang H, Nash PD, Newman DK, Nollau P, Pawson T, Renkema, GH, Saksela
K, Schiller MR, Shin DG, and Mayer BJ (2007) "High-Throughput
Phosphotyrosine Profiling Using SH2 Domains" Mol. Cell 26:899-915. PMID:
17588523
Schiller MR (2007) "Minimotif Miner, a computational tool to
investigate protein function, disease, and genetic diversity" Current
Protocols in Protein Science, Eds. Coligan JE, Dunn BM, Speicher DW,
Winkler H., Unit 2.12.1 - 2.12.14 John Wiley & Sons, Inc. PDF
Kaiser J (2006) News report about Minimotif miner website. Science
311:925 PDF
Balla S, Thapar V, Verma S, Luong T, Faghri T, Huang C-H, Rajasekaran
S, del Campo JJ, Shinn JH, Mohler WA, Maciejewski MW, Gryk MR,
Piccirillo B, Schiller SR, and Schiller MR (2006) Minimotif Miner, a
tool for investigating protein function. Nature Methods 3:175-177 PDF
PMID: 16489333
Schiller MR (2006) Coupling Receptor Tyrosine Kinases to Rho GTPases
- GEFs what's the link. Cell. Signaling 18:1834-1843. PDF PMID: 16725310
Schiller MR, Chakrabarti K, King GF, Schiller NI, Eipper BA, and
Maciejewski MW (2006) Regulation of RhoGEF activity by intramolecular
and intermolecular SH3 interactions J. Biol. Chem. 281:17774-17786 PDF
PMID: 16644733
Chakrabarti K, Lin R, Schiller NI, Wang Y, Fan Y-X, Koubi D, Rudkin
BB, Johnson GR, Schiller MR. (2005) A critical role for Kalirin in NGF
signaling through TrkA. Mol. Cell. Biol. 25:5106-5118. PDF PMID:
15923627
Penzes P, Beeser A, Chernoff J, Schiller MR, Eipper BA, Mains RE,
Huganir RL. (2003) Rapid induction of dendritic spine morphogenesis by
trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin.
Neuron 37: 263-74. PDF PMID: 12546821
|
