Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to Its Antley-Bixler Syndrome-like Phenotype

McCammon, Karen M.; Panda, Satya P.; Xia, Chuanwu; Kim, Jung-Ja P.; Moutinho, Daniela; Kranendonk, Michel; Auchus, Richard J.; Lafer, Eileen M.; Ghosh, Debashis; Martasek, Pavel; Kar, Rekha; Masters, Bettie Sue; Roman, Linda J.

doi:10.1074/jbc.M116.716019

Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to Its Antley-Bixler Syndrome-like Phenotype

Journal Article · Fri Aug 05 04:00:00 EDT 2016 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M116.716019· OSTI ID:1328798

McCammon, Karen M. ^[1]; Panda, Satya P. ^[1]; Xia, Chuanwu ^[2]; Kim, Jung-Ja P. ^[2]; Moutinho, Daniela ^[3]; Kranendonk, Michel ^[3]; Auchus, Richard J. ^[4]; Lafer, Eileen M. ^[1]; Ghosh, Debashis ^[5]; Martasek, Pavel ^[6]; Kar, Rekha ^[1]; Masters, Bettie Sue ^[1]; Roman, Linda J. ^[1]

Univ. of Texas Health Science Center, San Antonio, TX (United States)
Medical College of Wisconsin, Milwaukee, WI (United States)
Univ. Nova de Lisboa (Portugal)
Univ. of Michigan, Ann Arbor, MI (United States)
State Univ. of New York Upstate Medical Univ., Syracuse, NY (United States)
Charles Univ. in Prague (Czech Republic); General Univ. Hospital (Czech Republic)

Human NADPH-cytochrome P450 oxidoreductase (POR) gene mutations are associated with severe skeletal deformities and disordered steroidogenesis. The human POR mutation A287P presents with disordered sexual development and skeletal malformations. Difficult recombinant expression and purification of this POR mutant suggested that the protein was less stable than WT. The activities of cytochrome P450 17A1, 19A1, and 21A2, critical in steroidogenesis, were similar using our purified, full-length, unmodified A287P or WT POR, as were those of several xenobiotic-metabolizing cytochromes P450, indicating that the A287P protein is functionally competent in vitro, despite its functionally deficient phenotypic behavior in vivo. Differential scanning calorimetry and limited trypsinolysis studies revealed a relatively unstable A287P compared with WT protein, leading to the hypothesis that the syndrome observed in vivo results from altered POR protein stability. The crystal structures of the soluble domains of WT and A287P reveal only subtle differences between them, but these differences are consistent with the differential scanning calorimetry results as well as the differential susceptibility of A287P and WT observed with trypsinolysis. The relative in vivo stabilities of WT and A287P proteins were also examined in an osteoblast cell line by treatment with cycloheximide, a protein synthesis inhibitor, showing that the level of A287P protein post-inhibition is lower than WT and suggesting that A287P may be degraded at a higher rate. Overall, current studies demonstrate that, unlike previously described mutations, A287P causes POR deficiency disorder due to conformational instability leading to proteolytic susceptibility in vivo, rather than through an inherent flavin-binding defect.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); Fundação para a Ciência e a Tecnologia (FCT)

OSTI ID:: 1328798

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 39 Vol. 291; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
POR deficiency
cytochrome P450
cytochrome P450 oxidoreductase
diflavin oxidoreductase
flavoprotein
membrane protein
protein crystallization
protein stability
reductase

Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to Its Antley-Bixler Syndrome-like Phenotype

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