Matches in SemOpenAlex for { <https://semopenalex.org/work/W3157202223> ?p ?o ?g. }
- W3157202223 abstract "Abstract CBL is a RING type E3 ubiquitin ligase that functions as a negative regulator of tyrosine kinase signaling and loss of CBL E3 function is implicated in several forms of leukemia. The Src-like adaptor proteins (SLAP/SLAP2) bind to CBL and are required for CBL-dependent downregulation of antigen receptor, cytokine receptor, and receptor tyrosine kinase signaling. Despite the established role of SLAP/SLAP2 in regulating CBL activity, the nature of the interaction and the mechanisms involved are not known. To understand the molecular basis of the interaction between SLAP/SLAP2 and CBL, we solved the crystal structure of CBL tyrosine kinase binding domain (TKBD) in complex with SLAP2. The carboxy-terminal region of SLAP2 adopts an α-helical structure which binds in a cleft between the 4H, EF-hand, and SH2 domains of the TKBD. This SLAP2 binding site is remote from the canonical TKBD phospho-tyrosine peptide binding site but overlaps with a region important for stabilizing CBL in its autoinhibited conformation. In addition, binding of SLAP2 to CBL in vitro activates the ubiquitin ligase function of autoinhibited CBL. Disruption of the CBL/SLAP2 interface through mutagenesis demonstrated a role for this protein-protein interaction in regulation of CBL E3 ligase activity in cells. Our results reveal that SLAP2 binding to a regulatory cleft of the TKBD provides an alternative mechanism for activation of CBL ubiquitin ligase function." @default.
- W3157202223 created "2021-05-10" @default.
- W3157202223 creator A5003626890 @default.
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- W3157202223 date "2020-06-18" @default.
- W3157202223 modified "2023-10-15" @default.
- W3157202223 title "SLAP2 adaptor binding disrupts c-CBL autoinhibition to activate ubiquitin ligase function" @default.
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- W3157202223 doi "https://doi.org/10.1101/2020.06.18.159806" @default.
- W3157202223 hasPublicationYear "2020" @default.
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