期刊
CELL RESEARCH
卷 22, 期 2, 页码 372-386出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2011.119
关键词
APC; Asef; cell adhesion and cell migration; cancer; armadillo repeat domain
类别
资金
- National Natural Science Foundation of China [30900225, 30821005, 90919021]
- Shanghai Municipal Education Commission [09ZZ23]
- Shanghai Education Commission [08SG11]
- Shanghai Pujiang Program [09PJ1405500]
- Chinese Ministry of Education [109060]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
- National Comprehensive Technology Platforms for Innovative Drug RD [2009ZX09301-007]
- State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry (China)
- State Key Laboratory of Drug Research (China)
Adenomatous polyposis coli (APC) regulates cell-cell adhesion and cell migration through activating the APC-stimulated guanine nucleotide-exchange factor (GEF; Asef), which is usually autoinhibited through the binding between its Src homology 3 (SH3) and Dbl homology (DH) domains. The APC-activated Asef stimulates the small GTPase Cdc42, which leads to decreased cell-cell adherence and enhanced cell migration. In colorectal cancers, truncated APC constitutively activates Asef and promotes cancer cell migration and angiogenesis. Here, we report crystal structures of the human APC/Asef complex. We find that the armadillo repeat domain of APC uses a highly conserved surface groove to recognize the APC-binding region (ABR) of Asef, conformation of which changes dramatically upon binding to APC. Key residues on APC and Asef for the complex formation were mutated and their importance was demonstrated by binding and activity assays. Structural superimposition of the APC/Asef complex with autoinhibited Asef suggests that the binding between APC and Asef might create a steric clash between Asef-DH domain and APC, which possibly leads to a conformational change in Asef that stimulates its GEF activity. Our structures thus elucidate the molecular mechanism of Asef recognition by APC, as well as provide a potential target for pharmaceutical intervention against cancers.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据