title: The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction.
abstract: The brain-specific synaptic guanosine triphosphatase (GTPase)-activating protein (SynGAP) is important in synaptic plasticity. It shows dual specificity for the small guanine nucleotide-binding proteins Rap and Ras. Here, we show that RapGAP activity of SynGAP requires its C2 domain. In contrast to the isolated GAP domain, which does not show any detectable RapGAP activity, a fragment comprising the C2 and GAP domains (C2-GAP) stimulates the intrinsic GTPase reaction of Rap by approximately 1 x 10(4). The C2-GAP crystal structure, complemented by modelling and biochemical analyses, favours a concerted movement of the C2 domain towards the switch II region of Rap to assist in GTPase stimulation. Our data support a catalytic mechanism similar to that of canonical RasGAPs and distinct from the canonical RapGAPs. SynGAP presents the first example, to our knowledge, of a GAP that uses a second domain for catalytic activity, thus pointing to a new function of C2 domains.
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology and Developmental Biology Units, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pena
authors.forename: Michael
authors.initials: M
authors.lastname: Hothorn
authors.forename: Alexander
authors.initials: A
authors.lastname: Eberth
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kaschau
authors.forename: Annabel
authors.initials: A
authors.lastname: Parret
authors.forename: Lothar
authors.initials: L
authors.lastname: Gremer
authors.forename: Fabien
authors.initials: F
authors.lastname: Bonneau
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: Klaus
authors.initials: K
authors.lastname: Scheffzek
mesh_terms: D001921:Brain / Q000378:metabolism*; D002384:Catalysis; D003460:Crystallization; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D020668:rap GTP-Binding Proteins / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins
chemical_list: D020690:GTPase-Activating Proteins; C484739:SYNGAP1 protein, human; D020703:ras GTPase-Activating Proteins; D020668:rap GTP-Binding Proteins