The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction
Open accessAbstract
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.
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The SYNGAP1 C2 domain is necessary for Rap GTPase activity.
“In particular, two sites (G951 and T1043) map to the C-terminal domain (CTD) of GRIN2A, and one (R329) is located in the SYNGAP1 C2 domain, which is necessary for the Rap GTPase activity35 (Fig. 3).”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [35]
SynGAP's broad action on dendritic spine signaling arises from its central location in the NMDAR complex and its promiscuous GAP domain that can regulate various small G-proteins.
“This broad action of SynGAP on dendritic spine signaling arises from its central location in the NMDAR complex (Kennedy et al., 2005) and its endowment with a promiscuous GAP domain that can regulate a variety of small G-proteins (Krapivinsky et al., 2004; Pena et al., 2008).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Pena et al., 2008
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- Authors
- Pena, V., Hothorn, M., Eberth, A., Kaschau, N., Parret, A., Gremer, L., Bonneau, F., Ahmadian, M. R., & Scheffzek, K.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Düsseldorf University Hospital (DE)
- Max Planck Institute of Molecular Physiology (DE)
- Corresponding author
- Scheffzek, Klaus
- ORCID
- Venue
- The EMBO Reports
- Published
- 2008-03-07
- Volume
- 9
- Issue
- 4
- Pages
- 350-355
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC2288765
- OpenAlex
- W2136162554
- Cited by
- 101
- References
- 36
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 9 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 4 · 2013: 5 · 2012: 7
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- EMBO Reports (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- U.S. Department of Defense
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- SynGAP, C2 domain, Rap GTPases, GTPase-activating protein, RAPGAP, Ras GTPase-activating protein, switch II, synaptic plasticity, catalytic mechanism, small GTPases
- MeSH terms
- Brain, Catalysis, Crystallization, Humans, Kinetics, Models, Molecular, Protein Structure, Tertiary, rap GTP-Binding Proteins, GTPase-Activating Proteins, ras GTPase-Activating Proteins
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