Structure of Fam20A reveals a pseudokinase featuring unique disulfide pattern and inverted ATP-binding
- University of California, San Diego, United States
- Peking University, China
Abstract
Mutations in FAM20A cause tooth enamel defects known as Amelogenesis Imperfecta (AI) and renal calcification. We previously showed that Fam20A is a secretory pathway pseudokinase and allosterically activates the physiological casein kinase Fam20C to phosphorylate secreted proteins important for biomineralization (Cui et al., 2015). Here we report the nucleotide-free and ATP-bound structures of Fam20A. Fam20A exhibits a distinct disulfide bond pattern mediated by a unique insertion region. Loss of this insertion due to abnormal mRNA splicing interferes with the structure and function of Fam20A, resulting in AI. Fam20A binds ATP in the absence of divalent cations, and strikingly, ATP is bound in an inverted orientation compared to other kinases. Fam20A forms a dimer in the crystal, and residues in the dimer interface are critical for Fam20C activation. Together, these results provide structural insights into the function of Fam20A and shed light on the mechanism by which Fam20A mutations cause disease.
Data availability
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Crystal structure of Fam20APublicly available at the RCSB Protein Data Bank (accession no: 5WRR).
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Crystal Structure of Fam20A in complex with ATPPublicly available at the RCSB Protein Data Bank (accession no: 5WRS).
Article and author information
Author details
Funding
National Natural Science Foundation of China (31570735)
- Junyu Xiao
National Key Research & Development Plan (2016YFC0906000)
- Junyu Xiao
National Institutes of Health (DK018849)
- Jack E Dixon
National Institutes of Health (DK018024)
- Jack E Dixon
Human Frontier Science Program (LT000659/2013-L)
- Jixin Cui
Damon Runyon Cancer Research Foundation (DRG 2171-13)
- Michael A Cianfrocco
Howard Hughes Medical Institute
- Jack E Dixon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tony Hunter, Salk Institute for Biological Studies, United States
Version history
- Received: December 8, 2016
- Accepted: April 20, 2017
- Accepted Manuscript published: April 22, 2017 (version 1)
- Version of Record published: May 2, 2017 (version 2)
Copyright
© 2017, Cui et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of Fam20A reveals a pseudokinase featuring unique disulfide pattern and inverted ATP-binding
eLife 6:e23990.
https://doi.org/10.7554/eLife.23990
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