Academic Editor: Graham Pawelec
The title usage of Unde venisti ‘from where have you come’ is from a now dead language (Latin) that foundationally influenced modern English (not the major influence, but an essential formative one). This is an apt analogy for how both the ancient eukaryotic and eumetazoan functions of PGRMC proteins (PGRMC1 and PGRMC2 in mammals) probably influence modern human biology: via a formative trajectory from an evolutionarily foundational fulcrum. There is an arguable probability, although not a certainty, that PGRMC-like proteins were involved in eukaryogenesis. If so, then the proto-eukaryotic ancestral protein is modelled as having initiated the oxygen-induced and CYP450 (Cytochrome P450)-mediated synthesis of sterols in the endoplasmic reticulum to regulate proto-mitochondrial activity and heme homeostasis, as well as having enabled sterol transport between endoplasmic reticulum (ER) and mitochondria membranes involving the actin cytoskeleton, transport of heme from mitochondria, and possibly the regulation/origins of mitosis/meiosis. Later, during animal evolution, the last eumetazoan common ancestor (LEUMCA) acquired PGRMC phosphorylated tyrosines coincidentally with the gastrulation organizer, Netrin/deleted in colorectal carcinoma (DCC) signaling, muscle fibers, synapsed neurons, and neural recovery via a sleep-like process. Modern PGRMC proteins regulate multiple functions, including CYP450-mediated steroidogenesis, membrane trafficking, heme homeostasis, glycolysis/Warburg effect, fatty acid metabolism, mitochondrial regulation, and genomic CpG epigenetic regulation of gene expression. The latter imposes the system of differentiation status-sensitive cell-type specific proteomic complements in multi-tissued descendants of the LEUMCA. This paper attempts to trace PGRMC functions through time, proposing that key functions were involved in early eukaryotes, and were later added upon in the LEUMCA. An accompanying paper considers the implications of this awareness for human health and disease.
- PGRMC proteins are members of the membrane-associated progesterone receptor (MAPR) family.
- A gene encoding the first MAPR protein was acquired from a prokaryotic cytb5M gene very early in eukaryotic evolution.
- The MAPR interhelical insertion region (MIHIR) is a eukaryotic invention.
- PGRMC functions related to heme and steroid biology and membrane trafficking may reflect MAPR metabolic regulatory pathways of ancient eukaryotes.
- In animal evolution, the last eumetazoan common ancestor (LEUMCA) had acquired an extended PGRMC C-terminus, and the combination of tyrosine-phosphorylated cognates to human PGRMC1 Y139 and & Y180.
- Y139 is present in the MIHIR, which in PGRMC1 contains a conserved negatively charged predicted amphipathic alpha helix with coiled-coil properties. The MIHIR is hypothesized to be involved with actomyosin cytoskeletal interactions and membrane trafficking, and it is proposed that heme occupancy and MIHIR function will be mutually regulatable.
- Y180 forms part of in a C-terminal signaling motif that is recognizably conserved in eumetazoans, and therefore is hypothesized to be involved in functionality that appeared in the LEUMCA.
- PGRMC1 phosphorylation status affects pleiotropic pathways involved with metabolism, PI3K/Akt activity, NAD homeostasis, CpG epigenetic status, and more.
- It is argued that ancient MAPR metabolic regulatory processes embody PGRMC proteins as fulcrum points around which powerful cell biological effects can be leveraged.