3BUM

Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Sprouty2

3BUM の概要

• エントリーDOI: 10.2210/pdb3bum/pdb
• 関連するPDBエントリー: 3BUN 3BUO 3BUW 3BUX
• 分子名称: Protein sprouty homolog 2, E3 ubiquitin-protein ligase CBL (3 entities in total)
• 機能のキーワード: ligase, signal transduction, proto-oncogene, complex, cytoplasm, developmental protein, membrane, microtubule, polymorphism, calcium, metal-binding, phosphoprotein, sh2 domain, ubl conjugation pathway, zinc, zinc-finger
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 39766.65

構造登録者

Ng, C.,Jackson, A.R.,Buschdorf, P.J.,Sun, Q.,Guy, R.G.,Sivaraman, J. (登録日: 2008-01-03, 公開日: 2008-02-26, 最終更新日: 2024-10-30)

主引用文献

Ng, C.,Jackson, R.A.,Buschdorf, J.P.,Sun, Q.,Guy, G.R.,Sivaraman, J.
Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates
Embo J., 27:804-816, 2008

PubMed Abstract: The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins.

PubMed: 18273061
DOI: 10.1038/emboj.2008.18

実験手法

X-RAY DIFFRACTION (2 Å)