Progesterone receptor membrane component 1: a conserved eukaryotic protein with multiple and stratified disease-relevant functions in cell and organismal biology

Thejer BM1,2, Teakel SL1, Marama M1, Fang J1, Gurusinghe S3, Quinn JC3, Weston PA3, Weston LA3, Forwood JK1 and Cahill MA1

  1. School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia.
  2. Department of Biology, College of Science, University of Wasit, Wasit, Iraq.
  3. Graham Centre for Agricultural Innovation, Charles Sturt University, Wagga Wagga, NSW 2678, Australia.

PGRMC1 is the archetypical member of the Membrane Associated Progesterone Receptor (MAPR) family of cytochrome b5 (cytb5) domain proteins, of which animals have three gene subfamilies: pgrc, nenf (Neudesin) and neufc (Neuferricin). We show that all three MAPR genes were present in the ancestor of Opisthokonts: the eukaryotic clade including yeasts and animals. MAPR proteins are more closely related to archaebacterial than to alpha-proteobacterial cytb5 proteins. Eukaryotic cytb5 is related to alpha-proteobacterial genes. Lanosterol is the first sterol produced from squalene cyclisation. PGRMC1-like proteins regulate CyP51A1 lanosterol 14-alpha demethylase enzymes from yeast to humans. Both squalene cyclase and CyP51A1 are of bacterial origin, whereas PGRMC1 is of archaebacterial origin. Cholesterol dramatically affects the properties of mitochondrial membranes, and the first step of animal steroid hormone synthesis takes place there, where cholesterol is modified to the first progestogen, pregnenolone. PGRMC1 confers progestogen-responsiveness to cells, and is also a member of the Insig/SCAP complex which regulates SREBP1 to induce genes associated with fatty-acid catabolism, and SREBP2 to activate the mevalonate pathway leading to sterol production. This suggests a model where PGRMC1 function may reflect the regulatory interplay between the proto-eukaryotic archaebacterial host cell and its proto-mitochondrial bacterial endosymbiont at the root of eukaryotic evolution. PGRMC1 also acquired tyrosine phosphorylation sites during animal evolution concurrently with the appearance of striated muscle and nerve synapses, and before bilateral body plan. PGRMC1 phosphorylation differences exist between cancers, and it is tyrosine phosphorylated in post-synaptic densities. Migration of embryonic nerve cord axons requires PGRMC1 from nematodes to mammals, and PGRMC1 synaptic function is required for the synaptorestorative effects of ElaytaTM, a promising potential Alzheimers drug. Our data provide exciting new insights into PGRMC1 function in animal and disease biology.