5AXI

Crystal structure of Cbl-b TKB domain in complex with Cblin

5AXI の概要

• エントリーDOI: 10.2210/pdb5axi/pdb
• 分子名称: E3 ubiquitin-protein ligase CBL-B, Cblin, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: ubquitin ligase, phosphopeptide, cblin, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 108648.26

構造登録者

Ohno, A.,Maita, N.,Ochi, A.,Nakao, R.,Nikawa, T. (登録日: 2015-07-29, 公開日: 2016-03-02, 最終更新日: 2024-11-13)

主引用文献

Ohno, A.,Ochi, A.,Maita, N.,Ueji, T.,Bando, A.,Nakao, R.,Hirasaka, K.,Abe, T.,Teshima-Kondo, S.,Nemoto, H.,Okumura, Y.,Higashibata, A.,Yano, S.,Tochio, H.,Nikawa, T.
Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin
Arch.Biochem.Biophys., 594:1-7, 2016

PubMed Abstract: Cbl-b is a RING-type ubiquitin ligase. Previously, we showed that Cbl-b-mediated ubiquitination and proteosomal degradation of IRS-1 contribute to muscle atrophy caused by unloading stress. The phospho-pentapeptide DGpYMP (Cblin) mimics Tyr612-phosphorylated IRS-1 and inhibits the Cbl-b-mediated ubiquitination and degradation of IRS-1 in vitro and in vivo. In this study, we confirmed the direct interaction between Cblin and the TKB domain of Cbl-b using NMR. Moreover, we showed that the shortened tripeptide GpYM also binds to the TKB domain. To elucidate the inhibitory mechanism of Cblin, we solved the crystal structure of the TKB-Cblin complex at a resolution of 2.5 Å. The pY in Cblin inserts into a positively charged pocket in the TKB domain via hydrogen-bond networks and hydrophobic interactions. Within this complex, the Cblin structure closely resembles the TKB-bound form of another substrate-derived phosphopeptide, Zap-70-derived phosphopeptide. These peptides lack the conserved intrapeptidyl hydrogen bond between pY and a conserved residue involved in TKB-domain binding. Instead of the conserved interaction, these peptides specifically interact with the TKB domain. Based on this binding mode of Cblin to the TKB domain, we can design drugs against unloading-mediated muscle atrophy.

PubMed: 26874193
DOI: 10.1016/j.abb.2016.02.014

実験手法

X-RAY DIFFRACTION (2.5 Å)