4CVH

Crystal structure of human isoprenoid synthase domain-containing protein

Summary for 4CVH

• Entry DOI: 10.2210/pdb4cvh/pdb
• Descriptor: ISOPRENOID SYNTHASE DOMAIN-CONTAINING PROTEIN, MAGNESIUM ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm, cytosol : A4D126
• Total number of polymer chains: 1
• Total formula weight: 46227.19

Authors

Kopec, J.,Froese, D.S.,Krojer, T.,Newman, J.,Kiyani, W.,Goubin, S.,Strain-Damerell, C.,Vollmar, M.,von Delft, F.,Burgess-Brown, N.,Arrowsmith, C.,Edwards, A.,Bountra, C.,Lefeber, D.J.,Yue, W.W. (deposition date: 2014-03-27, release date: 2015-02-04, Last modification date: 2024-05-08)

Primary citation

Riemersma, M.,Froese, D.S.,Van Tol, W.,Engelke, U.F.,Kopec, J.,Van Scherpenzeel, M.,Ashikov, A.,Krojer, T.,von Delft, F.,Tessari, M.,Buczkowska, A.,Swiezewska, E.,Jae, L.T.,Brummelkamp, T.R.,Manya, H.,Endo, T.,Van Bokhoven, H.,Yue, W.W.,Lefeber, D.J.
Human Ispd is a Cytidyltransferase Required for Dystroglycan O-Mannosylation.
Chem.Biol., 22:1643-, 2015

PubMed 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.

PubMed: 26687144
DOI: 10.1016/J.CHEMBIOL.2015.10.014

Experimental method

X-RAY DIFFRACTION (2.39 Å)