INHIBITOR OF APOPTOSIS PROTEINS: DOMAIN ORGANIZATION AND CONFORMATIONAL REARRANG

凋亡蛋白抑制剂：结构域组织和构象重排

• 批准号: 8362368
• 负责人: CHARLES EIGENBROT
• 金额: $ 0.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362368
• 关键词: Apoptosis Inhibitor; Apoptotic; Baculoviruses; Binding; C-terminal; Cell Death; DNA Sequence Rearrangement; Distant; Event; Family member; Funding; Grant; Inhibition of Apoptosis; Molecular Conformation; Molecular Sieve Chromatography; Monitor; National Center for Research Resources; Principal Investigator; Protein Binding Domain; Proteins; Radiation; Research; Research Infrastructure; Resources; Source; Stimulus; Tertiary Protein Structure; Ubiquitination; United States National Institutes of Health; blocking factor; cost; dimer; gel electrophoresis; inhibitor-of-apoptosis protein; monomer; nephelometry; response; small molecule; structural biology; ubiquitin-protein ligase

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 in response to a variety of stimuli. IAP family members contain a variable number of protein-protein interaction domains in addition to a C-terminal RING domain that confers E3 ubiquitin ligase activity to the IAP proteins. Binding of small molecule antagonists to select baculovirus IAP repeats (BIR) within cellular IAPs (cIAPs) promotes cIAP auto-ubiquitination and subsequent proteasomal degradation, thereby releasing cIAP inhibition of apoptosis. The means by which this binding event in turn influences E3 ligase activity within the distant RING domain remains unclear. One simple hypothesis is that antagonist binding causes the cIAP protein to undergo a structural rearrangement from a "closed" to an "open" conformation, which is then competent to form active RING-RING dimers. In the "closed" state this dimer interface is inaccessible and active dimers cannot form. In support of this hypothesis, we find that addition of antagonist to purified, cIAP1 monomers causes dimer formation, as monitored by native gel electrophoresis, size exclusion chromatography and dynamic light scattering measurements.

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