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Structure paper

タイトル	Tubulin code eraser CCP5 binds branch glutamates by substrate deformation.
ジャーナル・号・ページ	Nature, Vol. 631, Issue 8022, Page 905-912, Year 2024
掲載日	2024年7月17日
著者	Jiayi Chen / Elena A Zehr / James M Gruschus / Agnieszka Szyk / Yanjie Liu / Martin E Tanner / Nico Tjandra / Antonina Roll-Mecak /
PubMed 要旨	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 ...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.
リンク	Nature / PubMed:39020174
手法	EM (単粒子) / X線回折
解像度	1.8 - 3.6 Å
構造データ	EMDB-42948: Microtubule protofilament reconstruction in CCP5:microtubule class#1 complex 手法: EM (単粒子) / 解像度: 3.0 Å 42950 8v3q EMDB-42950, PDB-8v3q: Structure of CCP5 class1 手法: EM (単粒子) / 解像度: 3.1 Å 42951 8v3r EMDB-42951, PDB-8v3r: Structure of CCP5 class2 手法: EM (単粒子) / 解像度: 3.4 Å 42952 8v3s EMDB-42952, PDB-8v3s: Structure of CCP5 class3 手法: EM (単粒子) / 解像度: 3.6 Å 42971 8v4k EMDB-42971, PDB-8v4k: CCP5 in complex with microtubules class1 手法: EM (単粒子) / 解像度: 3.1 Å 42972 8v4l EMDB-42972, PDB-8v4l: CCP5 in complex with microtubules class2 手法: EM (単粒子) / 解像度: 2.9 Å 42973 8v4m EMDB-42973, PDB-8v4m: CCP5 in complex with microtubules class3 手法: EM (単粒子) / 解像度: 3.0 Å EMDB-44544: Microtubule protofilament reconstruction in CCP5:microtubule class#2 complex 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-44545: Microtubule Protofilament reconstruction in CCP5:microtubule class#3 complex 手法: EM (単粒子) / 解像度: 3.2 Å PDB-8v3m: CCP5 apo structure 手法: X-RAY DIFFRACTION / 解像度: 1.8 Å PDB-8v3n: CCP5 in complex with Glu-P-Glu transition state analog 手法: X-RAY DIFFRACTION / 解像度: 2.3 Å PDB-8v3o: CCP5 in complex with Glu-P-peptide 1 transition state analog 手法: X-RAY DIFFRACTION / 解像度: 2.3 Å PDB-8v3p: CCP5 in complex with Glu-P-peptide 2 transition state analog 手法: X-RAY DIFFRACTION / 解像度: 2.36 Å
化合物	ChemComp-MLT: D-MALATE / D-りんご酸 ChemComp-IMD: IMIDAZOLE / 1H-イミダゾ-ル-3-カチオン ChemComp-ZN: Unknown entry ChemComp-HOH: WATER PDB-1aag: Unknown entry ChemComp-K: Unknown entry / カリウムカチオン ChemComp-GLU: GLUTAMIC ACID / グルタミン酸 ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-GTP: GUANOSINE-5'-TRIPHOSPHATE / GTP / GTP, エネルギー貯蔵分子YM ChemComp-G2P: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GMPCPP / GMP-CPP, エネルギー貯蔵分子類似体YM
由来	sus scrofa (ブタ) homo sapiens (ヒト)
キーワード	HYDROLASE / carboxypeptidase deglutamylation branch glutamate removal microtubule / HYDROLASE/INHIBITOR / HYDROLASE-INHIBITOR complex / carboxypeptidase / deglutamylation / branch glutamate removal / microtubule / HYDROLASE/SUBSTRATE / HYDROLASE-SUBSTRATE complex / STRUCTURAL PROTEIN / HYDROLASE-SUBSTRATE / STRUCTURAL PROTEIN complex