5GZ8

Crystal structure of catalytic domain of Protein O-mannosyl Kinase in ligand-free form

Summary for 5GZ8

• Entry DOI: 10.2210/pdb5gz8/pdb
• Related: 5GZ9
• Descriptor: Protein O-mannose kinase (2 entities in total)
• Functional Keywords: sugar kinase, dystroglycanopathy, o-mannosylation, transferase
• Biological source: Mus musculus (Mouse)
• Cellular location: Endoplasmic reticulum membrane ; Single-pass type II membrane protein : Q3TUA9
• Total number of polymer chains: 1
• Total formula weight: 35213.11

Authors

Nagae, M.,Yamaguchi, Y. (deposition date: 2016-09-27, release date: 2017-03-29, Last modification date: 2024-10-16)

Primary citation

Nagae, M.,Mishra, S.K.,Neyazaki, M.,Oi, R.,Ikeda, A.,Matsugaki, N.,Akashi, S.,Manya, H.,Mizuno, M.,Yagi, H.,Kato, K.,Senda, T.,Endo, T.,Nogi, T.,Yamaguchi, Y.
3D structural analysis of protein O-mannosyl kinase, POMK, a causative gene product of dystroglycanopathy.
Genes Cells, 22:348-359, 2017

PubMed Abstract: Orchestration of the multiple enzymes engaged in O-mannose glycan synthesis provides a matriglycan on α-dystroglycan (α-DG) which attracts extracellular matrix (ECM) proteins such as laminin. Aberrant O-mannosylation of α-DG leads to severe congenital muscular dystrophies due to detachment of ECM proteins from the basal membrane. Phosphorylation at C6-position of O-mannose catalyzed by protein O-mannosyl kinase (POMK) is a crucial step in the biosynthetic pathway of O-mannose glycan. Several mis-sense mutations of the POMK catalytic domain are known to cause a severe congenital muscular dystrophy, Walker-Warburg syndrome. Due to the low sequence similarity with other typical kinases, structure-activity relationships of this enzyme remain unclear. Here, we report the crystal structures of the POMK catalytic domain in the absence and presence of an ATP analogue and O-mannosylated glycopeptide. The POMK catalytic domain shows a typical protein kinase fold consisting of N- and C-lobes. Mannose residue binds to POMK mainly via the hydroxyl group at C2-position, differentiating from other monosaccharide residues. Intriguingly, the two amino acid residues K92 and D228, interacting with the triphosphate group of ATP, are donated from atypical positions in the primary structure. Mutations in this protein causing muscular dystrophies can now be rationalized.

PubMed: 28251761
DOI: 10.1111/gtc.12480

Experimental method

X-RAY DIFFRACTION (2.5 Å)