Beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy.

Autor:	Pakharukova N; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA.; Howard Hughes Medical Institute, Duke University Medical Center; Durham, NC 27710, USA., Thomas BN; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA.; Howard Hughes Medical Institute, Duke University Medical Center; Durham, NC 27710, USA., Bansia H; Structural Biology Initiative, CUNY Advanced Science Research Center; New York, NY 10031, USA., Li L; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA., Abzalimov RR; Structural Biology Initiative, CUNY Advanced Science Research Center; New York, NY 10031, USA., Kim J; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA., Kahsai AW; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA., Pani B; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA., Bassford DK; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA.; Howard Hughes Medical Institute, Duke University Medical Center; Durham, NC 27710, USA., Liu S; Structural Biology Initiative, CUNY Advanced Science Research Center; New York, NY 10031, USA., Zhang X; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA., des Georges A; Structural Biology Initiative, CUNY Advanced Science Research Center; New York, NY 10031, USA.; Department of Chemistry and Biochemistry, City College of New York; New York, NY 10031, USA.; Biochemistry and Chemistry PhD Programs, Graduate Center, City University of New York; New York, NY 10031, USA., Lefkowitz RJ; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA.; Howard Hughes Medical Institute, Duke University Medical Center; Durham, NC 27710, USA.; Department of Biochemistry, Duke University Medical Center; Durham, NC 27710, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 06. Date of Electronic Publication: 2024 Aug 06.
DOI:	10.1101/2024.07.31.605623
Abstrakt:	Beta-arrestins (βarrs) are key regulators and transducers of G-protein coupled receptor signaling; however, little is known of how βarrs communicate with their downstream effectors. Here, we use cryo-electron microscopy to elucidate how βarr1 recruits and activates non-receptor tyrosine kinase Src. βarr1 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 βarr1 interacts with the aromatic surface of SH3 which is critical for Src autoinhibition, suggesting that βarr1 activates Src by SH3 domain displacement. Binding of SH3 to the central crest region induces structural rearrangements in the β-strand V, finger, and middle loops of βarr1 and interferes with βarr1 coupling to the receptor core potentially impacting receptor desensitization and downstream signaling. Competing Interests: Competing interests: The authors declare that they have no conflicts of interest with the contents of this article.
Databáze:	MEDLINE
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