8V3P

CCP5 in complex with Glu-P-peptide 2 transition state analog

8V3P の概要

• エントリーDOI: 10.2210/pdb8v3p/pdb
• 分子名称: Cytosolic carboxypeptidase-like protein 5, Tubulin beta-2A chain, ZINC ION, ... (4 entities in total)
• 機能のキーワード: carboxypeptidase, deglutamylation, branch glutamate removal, microtubule, hydrolase
• 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: 61141.76

構造登録者

Chen, J.,Zehr, E.A.,Gruschus, J.M.,Szyk, A.,Liu, Y.,Tanner, M.E.,Tjandra, N.,Roll-Mecak, A. (登録日: 2023-11-28, 公開日: 2024-07-17, 最終更新日: 2024-11-06)

主引用文献

Chen, J.,Zehr, E.A.,Gruschus, J.M.,Szyk, A.,Liu, Y.,Tanner, M.E.,Tjandra, N.,Roll-Mecak, A.
Tubulin code eraser CCP5 binds branch glutamates by substrate deformation.
Nature, 631:905-912, 2024

PubMed Abstract: Microtubule function is modulated by the tubulin code, diverse posttranslational modifications that are altered dynamically by writer and eraser enzymes. Glutamylation-the addition of branched (isopeptide-linked) glutamate chains-is the most evolutionarily widespread tubulin modification. It is introduced by tubulin tyrosine ligase-like enzymes and erased by carboxypeptidases of the cytosolic carboxypeptidase (CCP) family. Glutamylation homeostasis, achieved through the balance of writers and erasers, is critical for normal cell function, and mutations in CCPs lead to human disease. Here we report cryo-electron microscopy structures of the glutamylation eraser CCP5 in complex with the microtubule, and X-ray structures in complex with transition-state analogues. Combined with NMR analysis, these analyses show that CCP5 deforms the tubulin main chain into a unique turn that enables lock-and-key recognition of the branch glutamate in a cationic pocket that is unique to CCP family proteins. CCP5 binding of the sequences flanking the branch point primarily through peptide backbone atoms enables processing of diverse tubulin isotypes and non-tubulin substrates. Unexpectedly, CCP5 exhibits inefficient processing of an abundant β-tubulin isotype in the brain. This work provides an atomistic view into glutamate branch recognition and resolution, and sheds light on homeostasis of the tubulin glutamylation syntax.

PubMed: 39020174
DOI: 10.1038/s41586-024-07699-0

実験手法

X-RAY DIFFRACTION (2.36 Å)