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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-Å 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.

Original publication

DOI

10.1073/pnas.1110415108

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

15/11/2011

Volume

108

Pages

18672 - 18677

Keywords

Binding Sites, Biological Transport, Crystallography, X-Ray, Death Domain Receptor Signaling Adaptor Proteins, Guanine, Guanine Nucleotide Exchange Factors, Humans, Kinetics, Nucleotides, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, rab GTP-Binding Proteins, rab1 GTP-Binding Proteins