Journal
EMBO JOURNAL
Volume 32, Issue 3, Pages 369-384Publisher
WILEY
DOI: 10.1038/emboj.2012.353
Keywords
endoplasmic reticulum; membrane fusion; protein structure
Categories
Funding
- National Science Foundation [DMR-0225180]
- National Institutes of Health [RR-01646]
- NIH [P41 RR04224, T32 GM008267, T32 GM008500, R01 GM090320, 1F31 NS077650]
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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.
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