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Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2011 Nov 15; Vol. 108 (46), pp. 18672-7. Date of Electronic Publication: 2011 Nov 07. - Publication Year :
- 2011
-
Abstract
- 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.
- Subjects :
- Binding Sites
Biological Transport
Crystallography, X-Ray methods
Humans
Kinetics
Nucleotides chemistry
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
rab1 GTP-Binding Proteins chemistry
Death Domain Receptor Signaling Adaptor Proteins chemistry
Guanine chemistry
Guanine Nucleotide Exchange Factors chemistry
rab GTP-Binding Proteins chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 108
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 22065758
- Full Text :
- https://doi.org/10.1073/pnas.1110415108