4cvh

Crystal structure of human isoprenoid synthase domain-containing protein

Structural highlights

4cvh is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.39Å
Ligands:	CL, EDO, MG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ISPD_HUMAN Autosomal recessive limb-girdle muscular dystrophy due to ISPD deficiency;Congenital muscular dystrophy without intellectual disability;Walker-Warburg syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

ISPD_HUMAN Required for protein O-linked mannosylation. Probably acts as a nucleotidyltransferase involved in synthesis of a nucleotide sugar. Required for dystroglycan O-mannosylation.^[1] ^[2]

Publication Abstract from PubMed

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.

Human ISPD Is a Cytidyltransferase Required for Dystroglycan O-Mannosylation.,Riemersma M, Froese DS, van Tol W, Engelke UF, Kopec J, van Scherpenzeel M, Ashikov A, Krojer T, von Delft F, Tessari M, Buczkowska A, Swiezewska E, Jae LT, Brummelkamp TR, Manya H, Endo T, van Bokhoven H, Yue WW, Lefeber DJ Chem Biol. 2015 Dec 17;22(12):1643-52. doi: 10.1016/j.chembiol.2015.10.014. Epub , 2015 Dec 10. PMID:26687144^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Willer T, Lee H, Lommel M, Yoshida-Moriguchi T, de Bernabe DB, Venzke D, Cirak S, Schachter H, Vajsar J, Voit T, Muntoni F, Loder AS, Dobyns WB, Winder TL, Strahl S, Mathews KD, Nelson SF, Moore SA, Campbell KP. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet. 2012 May;44(5):575-80. doi: 10.1038/ng.2252. PMID:22522420 doi:https://dx.doi.org/10.1038/ng.2252
↑ Roscioli T, Kamsteeg EJ, Buysse K, Maystadt I, van Reeuwijk J, van den Elzen C, van Beusekom E, Riemersma M, Pfundt R, Vissers LE, Schraders M, Altunoglu U, Buckley MF, Brunner HG, Grisart B, Zhou H, Veltman JA, Gilissen C, Mancini GM, Delree P, Willemsen MA, Ramadza DP, Chitayat D, Bennett C, Sheridan E, Peeters EA, Tan-Sindhunata GM, de Die-Smulders CE, Devriendt K, Kayserili H, El-Hashash OA, Stemple DL, Lefeber DJ, Lin YY, van Bokhoven H. Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of alpha-dystroglycan. Nat Genet. 2012 May;44(5):581-5. doi: 10.1038/ng.2253. PMID:22522421 doi:https://dx.doi.org/10.1038/ng.2253
↑ Riemersma M, Froese DS, van Tol W, Engelke UF, Kopec J, van Scherpenzeel M, Ashikov A, Krojer T, von Delft F, Tessari M, Buczkowska A, Swiezewska E, Jae LT, Brummelkamp TR, Manya H, Endo T, van Bokhoven H, Yue WW, Lefeber DJ. 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. Epub , 2015 Dec 10. PMID:26687144 doi:https://dx.doi.org/10.1016/j.chembiol.2015.10.014

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Willer T, Lee H, Lommel M, Yoshida-Moriguchi T, de Bernabe DB, Venzke D, Cirak S, Schachter H, Vajsar J, Voit T, Muntoni F, Loder AS, Dobyns WB, Winder TL, Strahl S, Mathews KD, Nelson SF, Moore SA, Campbell KP. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet. 2012 May;44(5):575-80. doi: 10.1038/ng.2252. PMID:22522420 doi:https://dx.doi.org/10.1038/ng.2252

[2] Roscioli T, Kamsteeg EJ, Buysse K, Maystadt I, van Reeuwijk J, van den Elzen C, van Beusekom E, Riemersma M, Pfundt R, Vissers LE, Schraders M, Altunoglu U, Buckley MF, Brunner HG, Grisart B, Zhou H, Veltman JA, Gilissen C, Mancini GM, Delree P, Willemsen MA, Ramadza DP, Chitayat D, Bennett C, Sheridan E, Peeters EA, Tan-Sindhunata GM, de Die-Smulders CE, Devriendt K, Kayserili H, El-Hashash OA, Stemple DL, Lefeber DJ, Lin YY, van Bokhoven H. Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of alpha-dystroglycan. Nat Genet. 2012 May;44(5):581-5. doi: 10.1038/ng.2253. PMID:22522421 doi:https://dx.doi.org/10.1038/ng.2253

[3] Riemersma M, Froese DS, van Tol W, Engelke UF, Kopec J, van Scherpenzeel M, Ashikov A, Krojer T, von Delft F, Tessari M, Buczkowska A, Swiezewska E, Jae LT, Brummelkamp TR, Manya H, Endo T, van Bokhoven H, Yue WW, Lefeber DJ. 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. Epub , 2015 Dec 10. PMID:26687144 doi:https://dx.doi.org/10.1016/j.chembiol.2015.10.014

[1]

[2]

[3]

4cvh

Crystal structure of human isoprenoid synthase domain-containing protein

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools