title: SUMO-SIM interactions regulate the activity of RGSZ2 proteins.
abstract: The RGSZ2 gene, a regulator of G protein signaling, has been implicated in cognition, Alzheimer's disease, panic disorder, schizophrenia and several human cancers. This 210 amino acid protein is a GTPase accelerating protein (GAP) on Gαi/o/z subunits, binds to the N terminal of neural nitric oxide synthase (nNOS) negatively regulating the production of nitric oxide, and binds to the histidine triad nucleotide-binding protein 1 at the C terminus of different G protein-coupled receptors (GPCRs). We now describe a novel regulatory mechanism of RGS GAP function through the covalent incorporation of Small Ubiquitin-like MOdifiers (SUMO) into RGSZ2 RGS box (RH) and the SUMO non covalent binding with SUMO-interacting motifs (SIM): one upstream of the RH and a second within this region. The covalent attachment of SUMO does not affect RGSZ2 binding to GPCR-activated GαGTP subunits but abolishes its GAP activity. By contrast, non-covalent binding of SUMO with RH SIM impedes RGSZ2 from interacting with GαGTP subunits. Binding of SUMO to the RGSZ2 SIM that lies outside the RH does not affect GαGTP binding or GAP activity, but it could lead to regulatory interactions with sumoylated proteins. Thus, sumoylation and SUMO-SIM interactions constitute a new regulatory mechanism of RGS GAP function and therefore of GPCR cell signaling as well.
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Garzón
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Muñoz
authors.forename: Ana
authors.initials: A
authors.lastname: Vicente-Sánchez
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: García-López
authors.forename: Ricardo
authors.initials: R
authors.lastname: Martínez-Murillo
authors.forename: Thierry
authors.initials: T
authors.lastname: Fischer
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D020710:RGS Proteins; C532880:RGS17 protein, mouse; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D025841:Small Ubiquitin-Related Modifier Proteins