期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 26, 页码 10574-10579出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1309211110
关键词
amelogenesis imperfecta; Fam20A; hypophosphatemia; Fam20B; enamel renal syndrome
资金
- Office of Science, Office of Basic Energy Sciences of the US Department of Energy [DE-AC02-05CH11231]
- National Institutes of Health [DK018849, DK018024]
- National Institutes of Health/National Cancer Institute [T32 CA009523]
- National Institutes of Health
- National Institute of General Medical Sciences
- Howard Hughes Medical Institute
The family with sequence similarity 20 (Fam20) kinases phosphorylate extracellular substrates and play important roles in biomineralization. Fam20C is the Golgi casein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs. Mutations in Fam20C cause Raine syndrome, an osteosclerotic bone dysplasia. Here we report the crystal structure of the Fam20C ortholog from Caenorhabditis elegans. The nucleotide-free and Mn/ADP-bound structures unveil an atypical protein kinase-like fold and highlight residues critical for activity. The position of the regulatory alpha C helix and the lack of an activation loop indicate an architecture primed for efficient catalysis. Furthermore, several distinct elements, including the presence of disulfide bonds, suggest that the Fam20 family diverged early in the evolution of the protein kinase superfamily. Our results reinforce the structural diversity of protein kinases and have important implications for patients with disorders of biomineralization.
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