1YVH

Crystal Structure of the c-Cbl TKB Domain in Complex with the APS pTyr-618 Phosphopeptide

Summary for 1YVH

• Entry DOI: 10.2210/pdb1yvh/pdb
• Descriptor: CBL E3 ubiquitin protein ligase, 13-mer fragment of SH2 and PH domain-containing adapter protein APS, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: x-ray crystallography; phosphotyrosine; adapter protein, ligase, signaling protein, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P22681 Q9Z200
• Total number of polymer chains: 2
• Total formula weight: 39859.06

Authors

Hu, J.,Hubbard, S.R. (deposition date: 2005-02-15, release date: 2005-03-08, Last modification date: 2024-10-16)

Primary citation

Hu, J.,Hubbard, S.R.
Structural Characterization of a Novel Cbl Phosphotyrosine Recognition Motif in the APS Family of Adapter Proteins
J.Biol.Chem., 280:18943-18949, 2005

PubMed Abstract: The Cbl adapter proteins typically function to down-regulate activated protein tyrosine kinases and other signaling proteins by coupling them to the ubiquitination machinery for degradation by the proteasome. Cbl proteins bind to specific tyrosine-phosphorylated sequences in target proteins via the tyrosine kinase-binding (TKB) domain, which comprises a four-helix bundle, an EF-hand calcium-binding domain, and a non-conventional Src homology-2 domain. The previously derived consensus sequence for phosphotyrosine recognition by the Cbl TKB domain is NXpY(S/T)XXP (X denotes lesser residue preference), wherein specificity is conferred primarily by residues C-terminal to the phosphotyrosine. Cbl is recruited to and phosphorylated by the insulin receptor in adipose cells through the adapter protein APS. APS is phosphorylated by the insulin receptor on a C-terminal tyrosine residue, which then serves as a binding site for the Cbl TKB domain. Using x-ray crystallography, site-directed mutagenesis, and calorimetric studies, we have characterized the interaction between the Cbl TKB domain and the Cbl recruitment site in APS, which contains a sequence motif, RA(V/I)XNQpY(S/T), that is conserved in the related adapter proteins SH2-B and Lnk. These studies reveal a novel mode of phosphopeptide interaction with the Cbl TKB domain, in which N-terminal residues distal to the phosphotyrosine directly contact residues of the four-helix bundle of the TKB domain.

PubMed: 15737992
DOI: 10.1074/jbc.M414157200

Experimental method

X-RAY DIFFRACTION (2.05 Å)