Structural basis for conformational switching and GTP loading of the large G protein atlastin

被引:72
作者
Byrnes, Laura J. [1 ]
Singh, Avtar [2 ]
Szeto, Kylan [3 ]
Benvin, Nicole M.
O'Donnell, John P. [1 ]
Zipfel, Warren R. [2 ]
Sondermann, Holger [1 ]
机构
[1] Cornell Univ, Coll Vet Med, Dept Mol Med, Ithaca, NY 14853 USA
[2] Cornell Univ, Dept Biomed Engn, Ithaca, NY 14853 USA
[3] Cornell Univ, Dept Appl & Engn Phys, Ithaca, NY 14853 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
endoplasmic reticulum; membrane fusion; protein structure; HEREDITARY SPASTIC PARAPLEGIA; CRYSTAL-STRUCTURE; HOMOTYPIC FUSION; DYNAMIN; BINDING; DOMAIN; DIMERIZATION; MUTATIONS; HYDROLYSIS; REQUIRES;
D O I
10.1038/emboj.2012.353
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Atlastin, a member of the dynamin superfamily, is known to catalyse homotypic membrane fusion in the smooth endoplasmic reticulum (ER). Recent studies of atlastin have elucidated key features about its structure and function; however, several mechanistic details, including the catalytic mechanism and GTP hydrolysis-driven conformational changes, are yet to be determined. Here, we present the crystal structures of atlastin-1 bound to GDP center dot AlF4- and GppNHp, uncovering an intramolecular arginine finger that stimulates GTP hydrolysis when correctly oriented through rearrangements within the G domain. Utilizing Forster Resonance Energy Transfer, we describe nucleotide binding and hydrolysis-driven conformational changes in atlastin and their sequence. Furthermore, we discovered a nucleotide exchange mechanism that is intrinsic to atlastin's N-terminal domains. Our results indicate that the cytoplasmic domain of atlastin acts as a tether and homotypic interactions are timed by GTP binding and hydrolysis. Perturbation of these mechanisms may be implicated in a group of atlastin-associated hereditary neurodegenerative diseases.
引用
收藏
页码:369 / 384
页数:16
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