1YVH: Crystal Structure Of The C-Cbl Tkb Domain In Complex With The Aps Ptyr-618 Phosphopeptide

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.
PDB ID: 1YVHDownload
MMDB ID: 32563
PDB Deposition Date: 2005/2/15
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.05  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 1YVH: dimeric; determined by author and by software (PISA)
Molecular Components in 1YVH
Label Count Molecule
Proteins (2 molecules)
CBL E3 Ubiquitin Protein Ligase(Gene symbol: CBL)
Molecule annotation
13-mer Fragment of SH2 and PH Domain-containing Adapter Protein APS(Gene symbol: Sh2b2)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB