Structural studies on the pathological mechanism of dystroglycanopathy

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K18496
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Structural biochemistry
• Research Institution: The University of Tokyo (2016); Institute of Physical and Chemical Research (2015)
• Principal Investigator: Nagae Masamichi 東京大学, 大学院薬学系研究科(薬学部), 特任研究員 (60619873)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 糖鎖生物学 / X線結晶構造解析 / 生化学

Outline of Final Research Achievements

Congenital muscular dystrophy is a group of diseases caused by defects in O-mannose glycosylation of the alpha-subunit of dystroglycan and progressive weakness and wasting of skeletal muscle are commonly observed. Alpha-dystroglycan (a-DG) is a component of the dystrophin-glycoprotein complex of skeletal muscle cells and directly links several other components to the basement membrane. The abnormal O-mannosylation of a-DG leads to severe congenital muscular dystrophies due to detachment of extracellular matrix 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. In this project, we solved the crystal structures of POMK catalytic domain in the absence and presence of substrates. These structures provides atomic insights into catalytic reaction mechanism and substrate recognition. These results lead to clinical approach to this severe disease.

Free Research Field

構造生物化学