TY - JOUR
T1 - Structure and evolution of the Fam20 kinases
AU - Zhang, Hui
AU - Zhu, Qinyu
AU - Cui, Jixin
AU - Wang, Yuxin
AU - Chen, Mark J.
AU - Guo, Xing
AU - Tagliabracci, Vincent S.
AU - Dixon, Jack E.
AU - Xiao, Junyu
N1 - Funding Information:
We are grateful to the staff of the Shanghai Synchrotron Radiation Facility (beamline BL17U) and the National Facility for Protein Science Shanghai (beamline BL19U) for assistance with X-ray data collection. We thank Kathrein Roper for providing the A. queenslandica cDNA library, Rob Steele for validating the H. magnipapillata Fam20 sequence, and Xinquan Wang for providing the expression vector of endogly-cosidase F3. We thank Carolyn Worby and Sandra Wiley for their critical reading of the manuscript. Special thanks to Chen Song for insightful discussions. The work was supported by the National Key Research and Development Program of China (2017YFA0505200 and 2016YFC0906000) and the National Natural Science Foundation of China (31570735) to J.X, and the NIH grant R00DK099254 and Welch Foundation Grant I-1911 to V.S.T. Some of this work was carried out in Jack Dixon’s laboratory, and he would like to acknowledge support from the NIH (grants DK 18849 and 18024) and the Howard Hughes Medical Institute.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - The Fam20 proteins are novel kinases that phosphorylate secreted proteins and proteoglycans. Fam20C phosphorylates hundreds of secreted proteins and is activated by the pseudokinase Fam20A. Fam20B phosphorylates a xylose residue to regulate proteoglycan synthesis. Despite these wide-ranging and important functions, the molecular and structural basis for the regulation and substrate specificity of these kinases are unknown. Here we report molecular characterizations of all three Fam20 kinases, and show that Fam20C is activated by the formation of an evolutionarily conserved homodimer or heterodimer with Fam20A. Fam20B has a unique active site for recognizing Galβ1-4Xylβ1, the initiator disaccharide within the tetrasaccharide linker region of proteoglycans. We further show that in animals the monomeric Fam20B preceded the appearance of the dimeric Fam20C, and the dimerization trait of Fam20C emerged concomitantly with a change in substrate specificity. Our results provide comprehensive structural, biochemical, and evolutionary insights into the function of the Fam20 kinases.
AB - The Fam20 proteins are novel kinases that phosphorylate secreted proteins and proteoglycans. Fam20C phosphorylates hundreds of secreted proteins and is activated by the pseudokinase Fam20A. Fam20B phosphorylates a xylose residue to regulate proteoglycan synthesis. Despite these wide-ranging and important functions, the molecular and structural basis for the regulation and substrate specificity of these kinases are unknown. Here we report molecular characterizations of all three Fam20 kinases, and show that Fam20C is activated by the formation of an evolutionarily conserved homodimer or heterodimer with Fam20A. Fam20B has a unique active site for recognizing Galβ1-4Xylβ1, the initiator disaccharide within the tetrasaccharide linker region of proteoglycans. We further show that in animals the monomeric Fam20B preceded the appearance of the dimeric Fam20C, and the dimerization trait of Fam20C emerged concomitantly with a change in substrate specificity. Our results provide comprehensive structural, biochemical, and evolutionary insights into the function of the Fam20 kinases.
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U2 - 10.1038/s41467-018-03615-z
DO - 10.1038/s41467-018-03615-z
M3 - Article
C2 - 29572475
AN - SCOPUS:85044346226
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1218
ER -