6XAR
Structure of CBL tyrosine kinase binding domain (TKBD) with C-terminal tail of Src-like kinase protein 2 (SLAP2)
Summary for 6XAR
| Entry DOI | 10.2210/pdb6xar/pdb |
| Descriptor | E3 ubiquitin-protein ligase CBL, Src-like-adapter 2, CALCIUM ION, ... (4 entities in total) |
| Functional Keywords | adaptor, e3 ubiquitin ligase, activation, complex, signaling protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 81880.28 |
| Authors | Wybenga-Groot, L.E.,McGlade, C.J. (deposition date: 2020-06-04, release date: 2021-03-03, Last modification date: 2023-10-18) |
| Primary citation | Wybenga-Groot, L.E.,Tench, A.J.,Simpson, C.D.,Germain, J.S.,Raught, B.,Moran, M.F.,McGlade, C.J. SLAP2 Adaptor Binding Disrupts c-CBL Autoinhibition to Activate Ubiquitin Ligase Function. J.Mol.Biol., 433:166880-166880, 2021 Cited by PubMed 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. PubMed: 33617900DOI: 10.1016/j.jmb.2021.166880 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.501 Å) |
Structure validation
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