期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 46, 页码 18672-18677出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1110415108
关键词
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资金
- National Institutes of Health (NIH) [GM080616, GM097348]
- National Science Foundation [MCB-0546353]
- American Heart Association [0940075N]
- Hellman Family Foundation
- Wellcome Trust [082467/Z/07/Z]
- Wellcome Trust [082467/Z/07/Z] Funding Source: Wellcome Trust
Rab GTPases are key regulators of membrane traffic pathways within eukaryotic cells. They are specifically activated by guanine nucleotide exchange factors (GEFs), which convert them from their inactive GDP-bound form to the active GTP-bound form. In higher eukaryotes, proteins containing DENN-domains comprise a major GEF family. Here we describe at 2.1-angstrom resolution the first structure of a DENN-domain protein, DENND1B-S, complexed with its substrate Rab35, providing novel insights as to how DENN-domain GEFs interact with and activate Rabs. DENND1B-S is bi-lobed, and interactions with Rab35 are through conserved surfaces in both lobes. Rab35 binds via switch regions I and II, around the nucleotide-binding pocket. Positional shifts in Rab residues required for nucleotide binding may lower its affinity for bound GDP, and a conformational change in switch I, which makes the nucleotide-binding pocket more solvent accessible, likely also facilitates exchange.
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