title: PGRMC1 regulation by phosphorylation: potential new insights in controlling biological activity
abstract: Progesterone receptor membrane component 1 (PGRMC1) is a multifunctional protein implicated in multiple pathologies, including cancer and Alzheimer's disease. The recently published structure of PGRMC1 revealed heme-mediated dimerization that directed the PGRMC1-dependent cytochrome P450-mediated detoxification of doxorubicin. We describe here how the PGRMC1 structure also enables important new insights into the possible regulation of PGRMC1 function by phosphorylation. Predicted regulatory interaction sites for SH2- and SH3-domain proteins are in non-structured regions that could be available to cytoplasmic enzymes. Further to the published interpretation, we suggest that phosphorylation of PGRMC1 at position Y113 may promote the attested membrane trafficking function of PGRMC1. To stimulate further experimentation, we also discuss that heme-mediated dimerization of PGRMC1 and membrane trafficking may be mutually exclusive functions. These roles could potentially be reciprocally regulated by phosphorylation/dephosphorylation at Y113. It follows that the phosphorylation status of PGRMC1 should be further explored in order to better understand many of its proposed biological functions.
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cahill
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia.
authors.forename: Jalal A
authors.initials: JA
authors.lastname: Jazayeri
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, Bosch Institute, University of Sydney, Sydney, NSW, Australia.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, Bosch Institute, University of Sydney, Sydney, NSW, Australia.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D011980:Receptors, Progesterone
keywords: SH2-domain; cancer; cytochrome P450; phosphorylation; signaling