期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms13047
关键词
-
资金
- Fonds der Chemischen Industrie, Germany
- Berlin Institute of Health (BIH) [11230009]
- NeuroCure [EXC 257]
- Cluster of Excellence RESOLV [EXC 1069]
- Collaborative Research Centre 740 - German Research Foundation-Deutsche Forschungsgemeinschaft (DFG) [SFB 740 TP B3, C1, C7, Z1, 740/2-11]
- National Genome Research Network-NGFN-Plus, IG NeuroNet [01GS08169-73]
- Program for Medical Genome Research of the German Federal Ministry of Education
- Research-Bundesministerium fur Bildung und Forschung (BMBF)
- European Consortium on Synaptic Protein Networks in Neurological and Psychiatric Diseases (EUROSPIN) [Health-F2-2009-241498]
- European Expertise Network on Building the Synapse (SynSys) by the European Union Framework Programme 7 [HEALTH-F2-2009-242167 23]
- Helmholtz Association through the Helmholtz Alliance on Systems Biology (MDC Systems Biology Network-MSBN)
- Helmholtz Alliance on Mental Aging-HeIMA [HA-215]
Interaction mapping is a powerful strategy to elucidate the biological function of protein assemblies and their regulators. Here, we report the generation of a quantitative interaction network, directly linking 14 human proteins to the AAA+ ATPase p97, an essential hexameric protein with multiple cellular functions. We show that the high-affinity interacting protein ASPL efficiently promotes p97 hexamer disassembly, resulting in the formation of stable p97: ASPL heterotetramers. High-resolution structural and biochemical studies indicate that an extended UBX domain (eUBX) in ASPL is critical for p97 hexamer disassembly and facilitates the assembly of p97: ASPL heterotetramers. This spontaneous process is accompanied by a reorientation of the D2 ATPase domain in p97 and a loss of its activity. Finally, we demonstrate that overproduction of ASPL disrupts p97 hexamer function in ERAD and that engineered eUBX polypeptides can induce cell death, providing a rationale for developing anti-cancer polypeptide inhibitors that may target p97 activity.
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