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

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.

• Authors: Naoyuki Kuwabara, Rieko Imae, Hiroshi Manya, Tomohiro Tanaka, Mamoru Mizuno, Hiroki Tsumoto, Motoi Kanagawa, Kazuhiro Kobayashi, Tatsushi Toda, Toshiya Senda, Tamao Endo, Ryuichi Kato
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 303 (01 16 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 31949166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glycopeptides
• Nucleoside Diphosphate Sugars
• Phosphates
• Polysaccharides
• cytidine diphosphate ribitol
• Ribitol
• FKRP protein, human
• Pentosyltransferases

Topics

• Catalytic Domain
• Crystallography, X-Ray
• Glycopeptides
• HEK293 Cells
• Humans
• Models, Molecular
• Muscular Dystrophies (genetics, metabolism)
• Nucleoside Diphosphate Sugars (chemistry, metabolism)
• Pentosyltransferases (chemistry, genetics, metabolism)
• Phosphates (metabolism)
• Polysaccharides (metabolism)
• Protein Conformation
• Protein Domains
• Ribitol (metabolism)