Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 46, Pages 18672-18677Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1110415108
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Funding
- 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
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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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