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TitleMechanism of beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateSep 27, 2025
AuthorsNatalia Pakharukova / Brittany N Thomas / Harsh Bansia / Linus Li / Dana K Bassford / Rinat R Abzalimov / Jihee Kim / Alem W Kahsai / Biswaranjan Pani / Kunhong Xiao / Roni Ochakovski / Shibo Liu / Xingdong Zhang / Seungkirl Ahn / Amedee des Georges / Robert J Lefkowitz /
PubMed AbstractBeta-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 report ...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 report the first structural insights into the fundamental mechanisms driving βarr-mediated signal transduction. Using cryo-electron microscopy, we elucidate how βarr1 recruits and activates the non-receptor tyrosine kinase Src, the first identified signaling partner of βarrs. βarr1 engages Src SH3 through two distinct sites, each employing a different recognition mechanism: a polyproline motif in the N-domain and a non-proline-based interaction in the central crest region. At both sites βarr1 interacts with the aromatic surface of SH3, disrupting the autoinhibited conformation of Src and directly triggering its allosteric activation. This structural evidence establishes βarr1 as an active regulatory protein rather than a passive scaffold and suggests a potentially general mechanism for βarr-mediated signaling across diverse effectors.
External linksbioRxiv / PubMed:39131402 / PubMed Central
MethodsEM (single particle)
Resolution3.34 - 3.47 Å
Structure data

44881

9bt8

EMDB-44881, PDB-9bt8:
Structure of Src in complex with beta-arrestin 1 revealing SH3 binding sites
Method: EM (single particle) / Resolution: 3.34 Å

45977

9cx3

EMDB-45977, PDB-9cx3:
Structure of SH3 domain of Src in complex with beta-arrestin 1
Method: EM (single particle) / Resolution: 3.47 Å

45982

9cx9

EMDB-45982, PDB-9cx9:
Structure of SH3 domain of Src in complex with beta-arrestin 1
Method: EM (single particle) / Resolution: 3.34 Å

Source
  • rattus norvegicus (Norway rat)
  • gallus gallus (chicken)
  • bacteriophage sp. (virus)
  • homo sapiens (human)
  • lama glama (llama)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / GPCR signaling / arrestin / Src / SH3 / SIGNALING PROTEIN-IMMUNE SYSTEM complex

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