PGRMC1 regulation by phosphorylation: potential new insights in controlling biological activity

Michael A. Cahill,Des R. Richardson,Jalal A. Jazayeri,Zaklina Kovacevic

doi:10.18632/oncotarget.10691

Michael A. Cahill, Des R. Richardson + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.10691

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Journal: Oncotarget	Publication Date: Jul 19, 2016
Citations: 53	License type: cc-by

Affiliation: Charles Sturt University, University of Sydney

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.

Highlights

The recent structure of Progesterone receptor membrane component 1 (PGRMC1) published in Nature Communications [4] confirmed many predictions reached by modeling PGRMC1 to the known structures of related proteins [1, 5, 6]
Heme-binding dimerizes the protein, which is required for its interaction with the cytochrome P450 enzyme that is responsible for the hydroxylation and inactivation of the anti-cancer chemotherapeutic, doxorubicin [4]
Consensus SH2-domain target sequences are centered on Y139 and Y180 (Figure 1A), and could require tyrosine phosphorylation for SH2proteins to bind [1, 8]

Summary

Introduction

The recent structure of PGRMC1 published in Nature Communications [4] confirmed many predictions reached by modeling PGRMC1 to the known structures of related proteins [1, 5, 6]. Heme-binding dimerizes the protein, which is required for its interaction with the cytochrome P450 enzyme that is responsible for the hydroxylation and inactivation of the anti-cancer chemotherapeutic, doxorubicin [4]. The apparent perplexing diversity of PGRMC1 function may be related to predicted binding sites for interacting SH2or SH3-domain signaling proteins (Figure 1A) [1, 7].

Results

Conclusion