Cell adhesion complexes are a bio-medically important class of multi-protein assemblies. They are involved in sensing Interactions between cells and their external environment, and then initiating and regulating intracellular signals that control cell migration, cell shape and functional organization, proliferation and survival, and gene expression. They are evolutionarily old, critical for normal development and homeostasis, and are defective in genetic diseases and cancer. Currently, there is a lack of a concerted effort to integrate available genomic (evolutionary) and structural information to rigorously solve the hierarchical structural organization of these multi-protein complexes at the atomic, meso and macro scale. A further barrier to progress is the availability of large amounts of purified proteins for multi-protein complex reconstitution since classical approaches are not feasible due to the unstable nature of complex protein assemblies. The Consortium will leverage high-throughput expression and structures of large sets of target families of proteins and signaling networks to understand the structural and functional organization of both cell-cell and cell-ECM adhesion complexes. The Consortium will integrate expertise in structural biology (X-ray crystallography, electron microscopy of in situ complexes), biochemistry and cell biology (in vitro reconstitution), chemistry and live cell imaging (in situ bio-sensors and caged proteins) by:
Specific Aim 1 : Define multi-protein interactions, stoichiometries and affinities in solution (Liddington, Weis).
Specific Aim 2 : Reconstitute multi-protein complexes on biological membranes (Ginsberg, Nelson).
Specific Aim 3 : Define structures of multi-protein complexes in situ, at a physiological environment (Hanein, Volkmann).
Specific Aim 4 : Analyze dynamic protein-protein interactions and assembly in live cells (Hahn).

Public Health Relevance

This is a critical area of Human Health. Cell adhesion complexes are important in all aspects of normal cell and tissue function, and are commonly defective in genetic diseases and cancers. Results will provide new understanding of how defects disrupt normal function and contribute to disease, and potentially identify new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01GM094663-03
Application #
8307835
Study Section
Special Emphasis Panel (ZGM1-CBB-0 (BC))
Program Officer
Ainsztein, Alexandra M
Project Start
2010-09-30
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$1,227,742
Indirect Cost
$233,363
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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