共 38 条
The mechanism of Torsin ATPase activation
被引:64
作者:
Brown, Rebecca S. H.
[1
]
Zhao, Chenguang
[1
]
Chase, Anna R.
[1
]
Wang, Jimin
[1
]
Schlieker, Christian
[1
]
机构:
[1] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA
来源:
基金:
美国国家科学基金会;
关键词:
DYT1;
dystonia;
nuclear envelope;
ATPase;
Torsin;
PLUS CHAPERONE CLPB;
NUCLEAR-ENVELOPE;
BINDING-PROTEIN;
AAA;
HYDROLYSIS;
WEB;
PROTEASES;
HOMOLOGY;
MACHINE;
GENE;
D O I:
10.1073/pnas.1415271111
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
Torsins are membrane-associated ATPases whose activity is dependent on two activating cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain-like LAP1 (LULL1). The mechanism bywhich these cofactors regulate Torsin activity has so far remained elusive. In this study, we identify a conserved domain in these activators that is predicted to adopt a fold resembling an AAA+ (ATPase associated with a variety of cellular activities) domain. Within these domains, a strictly conserved Arg residue present in both activating cofactors, but notably missing in Torsins, aligns with a key catalytic Arg found in AAA+ proteins. We demonstrate that cofactors and Torsins associate to form heterooligomeric assemblies with a defined Torsin-activator interface. In this arrangement, the highly conserved Arg residue present in either cofactor comes into close proximity with the nucleotide bound in the neighboring Torsin subunit. Because this invariant Arg is strictly required to stimulate Torsin ATPase activity but is dispensable for Torsin binding, we propose that LAP1 and LULL1 regulate Torsin ATPase activity through an active site complementation mechanism.
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页码:E4822 / E4831
页数:10
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