This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Inhibitors of apoptosis (IAPs) are anti-apoptotic factors that block cell death. IAPs contain protein-protein interaction domains and a C-terminal RING domain that confers E3 ubiquitin ligase activity. Binding of small molecule antagonists to cellular IAPs promotes cIAP auto-ubiquitination and subsequent proteasomal degradation, thereby releasing cIAP inhibition of apoptosis?a situation that may render some cancer therapies more effective. How the distant antagonist binding event influences the E3 ligase activity of the physically distinct RING domain is unclear. Our preliminary data support a hypothesis where antagonist binding leads to a structural rearrangement that permits formation of active RING-RING dimers. Moreover, antagonists can also promote a cIAP1 population of intermediate size;larger than monomer, yet smaller than a dimer. This form of cIAP1 is the dominant species in the presence of a particular monovalent antagonist and may represent the ?open?, but un-dimerized, form of the protein. We seek SAXS data from cIAP1 both in the absence and presence of small molecule antagonists. Htra1 is a multi-domain protease. A variant human Htra1 gene promotes overexpression and increases susceptibility to age-related macular degeneration. Htra1 is composed of four domains for which molecular shapes are known by homology and its protease activity requires formation of a non-covalent homotrimer of 1440 amino acids. The functional roles of the non-protease domains are not clear. The N-terminal domain composed of the IGFBP-rP and Kazal domains is absent in baterial homologues, suggesting a unique regulatory function. Our objective is to learn the domain locations in the trimer, potential domain interactions and domain oligomerization status. In addition, we have anti-Htra1 antibody fragments which may aid in SAXS analysis.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Stanford University
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