Early eukaryotic origins and metazoan elaboration of MAPR family proteins

[Display omitted] •All 3 animal MAPR families, PGRMC, NENF & NEUFC, were present in the common opisthokont ancestor.•Y-phosphorylated PGRMC1 Y139 & Y180 appeared concurrently with the gastrulation organiser.•The gastrulation organizer also appeared in the common ancestor of cnidarians and bilaterians.•PGRMC1 MIHIR has a predicted coiled-coil that would be disrupted by Y139 phosphorylation.•The C-terminus of each MAPR family was extended during the evolution from protists to animals. The membrane-associated progesterone receptor (MAPR) family consists of heme-binding proteins containing a cytochrome b5 (cytb5) domain characterized by the presence of a MAPR-specific interhelical insert region (MIHIR) between helices 3 and 4 of the canonical cytb5-domain fold. Animals possess three MAPR genes (PGRMC-like, Neuferricin and Neudesin). Here we show that all three animal MAPR genes were already present in the common ancestor of the opisthokonts (comprising animals and fungi as well as related single-celled taxa). All three MAPR genes acquired extensions C-terminal to the cytb5 domain, either before or with the evolution of animals. The archetypical MAPR protein, progesterone receptor membrane component 1 (PGRMC1), contains phosphorylated tyrosines Y139 and Y180. The combination of Y139/Y180 appeared in the common ancestor of cnidarians and bilaterians, along with an early embryological organizer and synapsed neurons, and is strongly conserved in all bilaterian animals. A predicted protein interaction motif in the PGRMC1 MIHIR is potentially regulated by Y139 phosphorylation. A multilayered model of animal MAPR function acquisition includes some pre-metazoan functions (e.g., heme binding and cytochrome P450 interactions) and some acquired animal-specific functions that involve regulation of strongly conserved protein interaction motifs acquired by animals (Metazoa). This study provides a conceptual framework for future studies, against which especially PGRMC1′s multiple functions can perhaps be stratified and functionally dissected.