Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy

被引：30

作者：

Kuwabara, Naoyuki ^{[1
]}

Imae, Rieko ^{[2
]}

Manya, Hiroshi ^{[2
]}

Tanaka, Tomohiro ^{[3
]}

Mizuno, Mamoru ^{[3
]}

Tsumoto, Hiroki ^{[4
]}

Kanagawa, Motoi ^{[5
]}

Kobayashi, Kazuhiro ^{[5
]}

Toda, Tatsushi ^{[5
,6
]}

Senda, Toshiya ^{[1
,7
]}

Endo, Tamao ^{[2
]}

Kato, Ryuichi ^{[1
,7
]}

机构：

[1] High Energy Accelerator Res Org, Inst Mat Struct Sci, Struct Biol Res Ctr, Tsukuba, Ibaraki 3050801, Japan

[2] Tokyo Metropolitan Geriatr Hosp & Inst Gerontol, Res Team Mech Aging, Mol Glycobiol, Itabashi Ku, Tokyo 1730015, Japan

[3] Noguchi Inst, Lab Glycoorgan Chem, Itabashi Ku, Tokyo 1730003, Japan

[4] Tokyo Metropolitan Geriatr Hosp & Inst Gerontol, Res Team Mech Aging, Proteome Res, Itabashi Ku, Tokyo 1730015, Japan

[5] Kobe Univ, Grad Sch Med, Div Mol Brain Sci, Kobe, Hyogo 6500017, Japan

[6] Univ Tokyo, Grad Sch Med, Dept Neurol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan

[7] SOKENDAI, Sch High Energy Accelerator Sci, Tsukuba, Ibaraki 3050801, Japan

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

日本学术振兴会;

关键词：

DYSTROGLYCAN FUNCTION; LARGE GLYCANS; MUTATIONS; GLYCOSYLATION; GENE; IDENTIFICATION; SYSTEM;

D O I：

10.1038/s41467-019-14220-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

alpha-Dystroglycan (alpha-DG) is a highly-glycosylated surface membrane protein. Defects in the O-mannosyl glycan of alpha-DG cause dystroglycanopathy, a group of congenital muscular dystrophies. The core M3 O-mannosyl glycan contains tandem ribitol-phosphate (RboP), a characteristic feature first found in mammals. Fukutin and fukutin-related protein (FKRP), whose mutated genes underlie dystroglycanopathy, sequentially transfer RboP from cytidine diphosphate-ribitol (CDP-Rbo) to form a tandem RboP unit in the core M3 glycan. Here, we report a series of crystal structures of FKRP with and without donor (CDP-Rbo) and/or acceptor [RboP-(phospho-)core M3 peptide] substrates. FKRP has N-terminal stem and C-terminal catalytic domains, and forms a tetramer both in crystal and in solution. In the acceptor complex, the phosphate group of RboP is recognized by the catalytic domain of one subunit, and a phosphate group on O-mannose is recognized by the stem domain of another subunit. Structure-based functional studies confirmed that the dimeric structure is essential for FKRP enzymatic activity.

引用

页数：11

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[1] Towards automated crystallographic structure refinement with phenix.refine [J].