9cx3
Structure of SH3 domain of Src in complex with beta-arrestin 1
Structural highlights
FunctionSRC_CHICK Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates involved in this process. When cells adhere via focal adhesions to the extra-cellular matrix, signals are transmitted by integrins into the cell and result in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN). Also active at the sites of cell-cell contact adherens junctions and at gap junctions. Implicated in the regulation of pre-mRNA-processing. Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus.[1] [2] Publication Abstract from PubMedBeta-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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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