Synaptic GAP and GEF Complexes Cluster Proteins Essential for GTP Signaling

Sci Rep. 2017 Jul 13;7(1):5272. doi: 10.1038/s41598-017-05588-3.

Abstract

GTPase-activating proteins (GAPs) and guanine exchange factors (GEFs) play essential roles in regulating the activity of small GTPases. Several GAPs and GEFs have been shown to be present at the postsynaptic density (PSD) within excitatory glutamatergic neurons and regulate the activity of glutamate receptors. However, it is not known how synaptic GAP and GEF proteins are organized within the PSD signaling machinery, if they have overlapping interaction networks, or if they associate with proteins implicated in contributing to psychiatric disease. Here, we determine the interactomes of three interacting GAP/GEF proteins at the PSD, including the RasGAP Syngap1, the ArfGAP Agap2, and the RhoGEF Kalirin, which includes a total of 280 interactions. We describe the functional properties of each interactome and show that these GAP/GEF proteins are highly associated with and cluster other proteins directly involved in GTPase signaling mechanisms. We also utilize Agap2 as an example of GAP/GEFs localized within multiple neuronal compartments and determine an additional 110 interactions involving Agap2 outside of the PSD. Functional analysis of PSD and non-PSD interactomes illustrates both common and unique functions of Agap2 determined by its subcellular location. Furthermore, we also show that these GAPs/GEFs associate with several proteins involved in psychiatric disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • GTPase-Activating Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Guanosine Triphosphate / metabolism*
  • Mental Disorders / metabolism*
  • Mental Disorders / pathology
  • Mice
  • Post-Synaptic Density / metabolism*
  • Protein Interaction Domains and Motifs
  • Signal Transduction
  • ras GTPase-Activating Proteins / metabolism*

Substances

  • Adap2 protein, mouse
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • KALRN protein, mouse
  • Syngap1 protein, mouse
  • ras GTPase-Activating Proteins
  • Guanosine Triphosphate