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Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin.
- Source :
-
ELife [Elife] 2013 Oct 01; Vol. 2, pp. e01279. Date of Electronic Publication: 2013 Oct 01. - Publication Year :
- 2013
-
Abstract
- Plexins are cell surface receptors that bind semaphorins and transduce signals for regulating neuronal axon guidance and other processes. Plexin signaling depends on their cytoplasmic GTPase activating protein (GAP) domain, which specifically inactivates the Ras homolog Rap through an ill-defined non-canonical catalytic mechanism. The plexin GAP is activated by semaphorin-induced dimerization, the structural basis for which remained unknown. Here we present the crystal structures of the active dimer of zebrafish PlexinC1 cytoplasmic region in the apo state and in complex with Rap. The structures show that the dimerization induces a large-scale conformational change in plexin, which opens the GAP active site to allow Rap binding. Plexin stabilizes the switch II region of Rap in an unprecedented conformation, bringing Gln63 in Rap into the active site for catalyzing GTP hydrolysis. The structures also explain the unique Rap-specificity of plexins. Mutational analyses support that these mechanisms underlie plexin activation and signaling. DOI:http://dx.doi.org/10.7554/eLife.01279.001.
- Subjects :
- Amino Acid Sequence
Animals
Catalytic Domain
Cell Adhesion Molecules genetics
Cell Adhesion Molecules metabolism
Crystallography, X-Ray
Gene Expression Regulation
Guanosine Triphosphate metabolism
Humans
Mice
Models, Molecular
Molecular Sequence Data
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Protein Binding
Protein Multimerization
Protein Structure, Secondary
Protein Structure, Tertiary
Sequence Alignment
Sequence Homology, Amino Acid
Signal Transduction
Zebrafish metabolism
Zebrafish Proteins genetics
Zebrafish Proteins metabolism
rap GTP-Binding Proteins genetics
rap GTP-Binding Proteins metabolism
Cell Adhesion Molecules chemistry
Guanosine Triphosphate chemistry
Nerve Tissue Proteins chemistry
Zebrafish genetics
Zebrafish Proteins chemistry
rap GTP-Binding Proteins chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 2
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 24137545
- Full Text :
- https://doi.org/10.7554/eLife.01279