View source for 9cx9


==Structure of SH3 domain of Src in complex with beta-arrestin 1==
<StructureSection load='9cx9' size='340' side='right'caption='[[9cx9]], [[Resolution|resolution]] 3.34&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9cx9]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9CX9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9CX9 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.34&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9cx9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9cx9 OCA], [https://pdbe.org/9cx9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9cx9 RCSB], [https://www.ebi.ac.uk/pdbsum/9cx9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9cx9 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ARRB1_RAT ARRB1_RAT] Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils.<ref>PMID:8553074</ref> <ref>PMID:9388255</ref> <ref>PMID:9822622</ref> <ref>PMID:10212203</ref> <ref>PMID:10347185</ref> <ref>PMID:9924018</ref> <ref>PMID:10747877</ref> <ref>PMID:10725339</ref> <ref>PMID:10995467</ref> <ref>PMID:11742073</ref> <ref>PMID:11579203</ref> <ref>PMID:11777902</ref> <ref>PMID:11901145</ref> <ref>PMID:12399592</ref> <ref>PMID:12519791</ref> <ref>PMID:12821670</ref> <ref>PMID:15173580</ref> <ref>PMID:15878855</ref> <ref>PMID:17594911</ref> <ref>PMID:18006496</ref> 
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== Publication Abstract from PubMed ==
Beta-arrestins (betaarrs) are key regulators and transducers of G-protein coupled receptor signaling; however, little is known of how betaarrs communicate with their downstream effectors. Here, we use cryo-electron microscopy to elucidate how betaarr1 recruits and activates non-receptor tyrosine kinase Src. betaarr1 binds Src SH3 domain via two distinct sites: a polyproline site in the N-domain and a non-proline site in the central crest region. At both sites betaarr1 interacts with the aromatic surface of SH3 which is critical for Src autoinhibition, suggesting that betaarr1 activates Src by SH3 domain displacement. Binding of SH3 to the central crest region induces structural rearrangements in the beta-strand V, finger, and middle loops of betaarr1 and interferes with betaarr1 coupling to the receptor core potentially impacting receptor desensitization and downstream signaling.

Beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy.,Pakharukova N, Thomas BN, Bansia H, Li L, Abzalimov RR, Kim J, Kahsai AW, Pani B, Bassford DK, Liu S, Zhang X, des Georges A, Lefkowitz RJ bioRxiv [Preprint]. 2024 Aug 6:2024.07.31.605623. doi: 10.1101/2024.07.31.605623. PMID:39131402<ref>PMID:39131402</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Gallus gallus]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Rattus norvegicus]]
[[Category: Bansia H]]
[[Category: Lefkowitz RJ]]
[[Category: Pakharukova N]]
[[Category: Des Georges A]]