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

Naoyuki Kuwabara, Rieko Imae, Hiroshi Manya, Tomohiro Tanaka, Mamoru Mizuno, Hiroki Tsumoto, Motoi Kanagawa, Kazuhiro Kobayashi, Tatsushi Toda, Toshiya Senda, Tamao Endo () and Ryuichi Kato ()
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Naoyuki Kuwabara: High Energy Accelerator Research Organization
Rieko Imae: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku
Hiroshi Manya: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku
Tomohiro Tanaka: The Noguchi Institute, Itabashi-ku
Mamoru Mizuno: The Noguchi Institute, Itabashi-ku
Hiroki Tsumoto: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku
Motoi Kanagawa: Kobe University Graduate School of Medicine
Kazuhiro Kobayashi: Kobe University Graduate School of Medicine
Tatsushi Toda: Kobe University Graduate School of Medicine
Toshiya Senda: High Energy Accelerator Research Organization
Tamao Endo: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku
Ryuichi Kato: High Energy Accelerator Research Organization

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract α-Dystroglycan (α-DG) is a highly-glycosylated surface membrane protein. Defects in the O-mannosyl glycan of α-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.

Date: 2020
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DOI: 10.1038/s41467-019-14220-z

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