Seminar: To be or not to be a pseudokinase—tales of two secretory pathway kinases



Dr Yunyu Xiao

Peking University


Eukaryotic protein kinases play essential roles in many cellular processes. Recently, a number of kinases functioning specifically in the secretory pathway have been uncovered. Fam20C is the genuine casein kinase and phosphorylates many secreted proteins to regulate biomineralization. Fam20A is highly similar to Fam20C; however, it functions as a pseudokinase to allosterically regulate Fam20C activity. The crystal structure of Fam20A reveals distinct positions of several important loops, which lock the protein in an inactive conformation. On the other hand, POMK was long thought to be a pseudokinase, due to the “absence” of key residues involved in ATP-binding and catalysis. It turned out to be a bona fide kinase and phosphorylates a mannose residue on a-dystroglycan in the lumen of the endoplasmic reticulum. The crystal structure of POMK reveals a composite catalytic site formed by residues located in unconventional positions, and the active site structure is further stabilized by a unique disulfide bond. These results provide important insights into the functional mechanism of these proteins, and highlight the structural diversity of secretory pathway kinases.