Human ISPD Is a Cytidyltransferase Required for Dystroglycan O-Mannosylation

Chem Biol. 2015 Dec 17;22(12):1643-52. doi: 10.1016/j.chembiol.2015.10.014.

Moniek Riemersma ¹, D Sean Froese ², Walinka van Tol ³, Udo F Engelke ⁴, Jolanta Kopec ², Monique van Scherpenzeel ³, Angel Ashikov ³, Tobias Krojer ², Frank von Delft ², Marco Tessari ⁵, Anna Buczkowska ⁶, Ewa Swiezewska ⁶, Lucas T Jae ⁷, Thijn R Brummelkamp ⁷, Hiroshi Manya ⁸, Tamao Endo ⁸, Hans van Bokhoven ⁹, Wyatt W Yue ¹⁰, Dirk J Lefeber ¹¹

Affiliations

1 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
2 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
3 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
4 Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
5 Institute for Molecules and Materials, Radboud University Nijmegen, 6525 ED Nijmegen, the Netherlands.
6 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5A Pawinskiego Street, 02-106 Warsaw, Poland.
7 Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
8 Molecular Glycobiology, Research Team for Mechanisms of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan.
9 Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
10 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: [email protected].
11 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: [email protected].

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

Abstract

A unique, unsolved O-mannosyl glycan on α-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 α-dystroglycan O-mannosylation in muscle and brain. Thereby, ISPD deficiency can be added to the growing list of tertiary dystroglycanopathies.

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