The Journal of Steroid Biochemistry and Molecular Biology
ReviewProgesterone receptor membrane component 1: An integrative review
Section snippets
Outline
This review will first discuss the biological circumstances in which PGRMC1 was initially encountered and identified, providing the context of nomenclatural synonyms described from various mammals, as well as for homologues in other organisms. Sections follow on subcellular localisation and interaction partners for the protein, as well as a consideration of potential ligands. Structural modelling using an Arabidopsis homologue is combined with structural motif prediction and consideration of
Cloning and nomenclature
Compiling a collection of literature on PGRMC1 is a daunting task because of its publication under so many synonyms from different biological contexts. The historical appearance of these synonyms is briefly reviewed in this section.
Nematode Vem-1
Pursuing the 1999 cloning of the rat CARO 2 antigen as VemaA (PGRMC1), in 2004 Runko and Kaprielian [26] published the C. elegans VEM-1 gene as the nematode homolog, which was identified by searching for homology to PGRMC1 and PGRMC2 within the C. elegans genome sequence. VEM-1 shared 37% amino acid identity with PGRMC1. A transgenic null mutation was constructed and interfered with neuron guidance and axon formation in a variety of neurons in the nematode ventral midline, which was the context
Sub-cellular localisation
PGRMC1 was first purified from rat liver (microsomal) membrane fractions [12], and was shown to cofractionate with the endoplasmic reticulum in liver extracts [28]. Perinuclear localisation, consistent with endoplasmic reticulum, was observed in MCF-7 cells [24]. Two more reports suggest a nuclear or chromosomal localisation for PGRMC1. As discussed below under the thematics of phosphorylation, Beausoleil et al. detected phosphopeptides from PGRMC1 in nuclear extracts of HeLa cells [40], and
Interaction partners
Intimately related to the theme of subcellular localisation is the identity of proteins with which PGRMC1 interacts. Some direct protein-interactions with PGRMC1 have been demonstrated in mammals, and others are strongly implied by their observation in processes in lower animals that are highly conserved in evolution. The evidence for PGRMC1 dimer formation is strong (i.e. that the protein interacts with itself). Thiele and colleagues from the Max Planck Institute of Molecular Cell Biology and
Potential ligands
PGRMC1 has been implicated in the binding of several ligands, all of which could yet prove to be of biological relevance.
Cytochrome b5 domain fold
Mifsud and Bateman recognised in 2002 that the MAPR family of which PGRMC1 is a member contains a cytochrome b5 domain fold [69]. In the same year, the NMR solution structure of the cytochrome b5-domain putative ligand binding domain of the Arabidopsis protein “Putative Steroid-Binding Protein” (Genbank Accession GI:40889041) was submitted by Suzuki and colleagues from the RIKEN Genomic Sciences Center, Yokohama, to the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data
PGRMC2
No treatment of PGRMC1 can be complete without consideration of its close relative, PGRMC2. Despite the preponderance of publications on PGRMC1 cited above, there has been practically nothing published regarding the function of PGRMC2. Gerdes et al. cloned the human gene in 1998 [18]. In 2004 Runko and Kaprielian recognised the human, murine and zebrafish variants of PGRMC2 which they named VemaB [27]. In 2005 Min et al. identified a gene they called hIZA2 which was similar to, yet slightly
Possible disease relevance
PGRMC1 was cloned as 25-DX as a dioxin-inducible gene, which suggests a possible function in stress-alleviation or stress response, an interpretation which seems to be supported by subsequent data. Progesterone has a neuroprotective effect. We have already seen that progesterone treatment of spinal chord-injured rats led to increased PGRMC1 expression in the rat spinal cord [48], and PGRMC1 is also expressed in brain regions involved in water homeostasis, where it is up-regulated after
Conclusions
Despite intensive efforts, the function of PGRMC1 remains unresolved. One possible model, somewhat incredibly compatible with all published information to date, is that PGRMC1 may even exert all its steroidogenic and metabolic effects by regulating the mevalonate pathway. In that case the conceptual preponderance of experiments to determine the nature of ligand binding, particularly of progesterone and heme, may be irrelevant for many PGRMC1 functions unless the ligand is a cholesterol
Note added in press
In February 2007 Hughes et al. from Johns Hopkins University in Baltimore, Vanderbilt University in Nashville, and Indiana University–Purdue University and Eli Lilly in Indianapolis reported that PGRMC1/Dap1 is necessary for cytochrome P450 function in humans and yeast. Schizosaccharomyces pombe Dap1 was shown to be “a hemoprotein that binds and positively regulates Cyp51A1 and Cyp61A1, two P450s required for sterol biosynthesis.” Loss of human PGRMC1 also reduced the activity of Cyp51A1, which
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