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Human ISPD Is a Cytidyltransferase Required for Dystroglycan O-Mannosylation

DOI: 10.1016/j.chembiol.2015.10.014 DOI Help
PMID: 26687144 PMID Help

Authors: Moniek Riemersma (Radboud University Medical Center) , Sean Froese (University of Oxford) , Walinka Van tol (Radboud University Medical Center) , Udo f Engelke (Radboud University Medical Center) , Jolanta Kopec (University of Oxford) , Monique Van scherpenzeel (Radboud University Medical Center) , Angel Ashikov (Radboud University Medical Center) , Tobias Krojer (Oxford University SGC) , Frank Von Delft (Diamond Light Source; University of Oxford) , Marco Tessari (Radboud University Nijmegen) , Anna Buczkowska (Polish Academy of Sciences) , Ewa Swiezewska (Polish Academy of Sciences) , Lucas t Jae (Netherlands Cancer Institute) , Thijn r Brummelkamp (Netherlands Cancer Institute) , Hiroshi Manya (Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology) , Tamao Endo (Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology) , Hans Van bokhoven (Radboud University Medical Center) , Wyatt Yue (University of Oxford) , Dirk j Lefeber (Radboud University Medical Center)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry & Biology , VOL 22 , PAGES 1643 - 1652

State: Published (Approved)
Published: December 2015

Abstract: A unique, unsolved O-mannosyl glycan on alpha-dystroglycan is essential for its interaction with protein ligands in the extracellular matrix. Defective O-mannosylation leads to a group of muscular dystrophies, called dystroglycanopathies. Mutations in isoprenoid synthase domain containing (ISPD) represent the second most common cause of these disorders, however, its molecular function remains uncharacterized. The human ISPD (hISPD) crystal structure showed a canonical N-terminal cytidyltransferase domain linked to a C-terminal domain that is absent in cytidyltransferase homologs. Functional studies demonstrated cytosolic localization of hISPD, and cytidyltransferase activity toward pentose phosphates, including ribulose 5-phosphate, ribose 5-phosphate, and ribitol 5-phosphate. Identity of the CDP sugars was confirmed by liquid chromatography quadrupole time-of-flight mass spectrometry and two-dimensional nuclear magnetic resonance spectroscopy. Our combined results indicate that hISPD is a cytidyltransferase, suggesting the presence of a novel human nucleotide sugar essential for functional alpha-dystroglycan O-mannosylation in muscle and brain. Thereby, ISPD deficiency can be added to the growing list of tertiary dystroglycanopathies.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography