Choose your partners for the next dance: implied PGRMC1 roles in membrane trafficking and mitochondrial modulation

Cahill, Michael A.

doi:10.1016/j.fertnstert.2020.01.029

Cited by 7 publications

(9 citation statements)

References 6 publications

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“…Heme interacting Y107 (H-bond) and Y113 (tyrosinate heme chelation), and multiple hydrophobic interactions with heme (G124, L125, F128, C129 and L130) are N-terminal to the MIHIR, whereas propionate H-bond forming K163 and Y164 are C-terminal to the MIHIR (Fig. 6C) [4,180]. We can then imagine that the MIHIR, or proteins interacting with it, could exert strong allosteric influence over heme affinity, and probably vice-versa.…”

Section: Potential Early Eukaryotic Mapr Functions Deduced From Moder...mentioning

confidence: 99%

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

Cahill¹

2022

Front. Biosci. (Landmark Ed)

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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 oxygeninduced 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.

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Section: Potential Early Eukaryotic Mapr Functions Deduced From Moder...mentioning

confidence: 99%

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

Cahill¹

2022

Front. Biosci. (Landmark Ed)

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“…Y139 is situated in the MIHIR, and represents one of the heptad repeat residues of a predicted coiled-coil protein interaction domain that shares similarity with coiled-coil motifs from various myosin proteins. Thereby, phosphorylation of Y139 would be predicted to disrupt coiled-coil interactions, and permit new interactions with phosphotyrosine-binding SH2-domain proteins (Cahill, 2020;Hehenberger et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…PGRMC1 is immunoprecipitated in protein complexes along with with components of the actin cytoskeleton (Salsano et al, 2020;Teakel et al, 2020), which is in turn involved in the membrane trafficking of exo-and endocytosis (Meunier and Gutierrez, 2016). It follows that evolutionarily ancient actin-cytoskeletal interactions of the PGRMC1 MIHIR sequence could be modulated by tyrosine phosphorylation that was acquired by eumetazoans at the same time as the gastrulation organizer developed (Cahill, 2020).…”

Section: Introductionmentioning

confidence: 99%

MAPR origins reveal a new class of prokaryotic cytochrome b₅ proteins and possible role in eukaryogenesis

Tamarit

Teakel

Marama

et al. 2021

Preprint

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The multiple functions of PGRMC1, the archetypal heme-binding eukaryotic MAPR family member, include steroidogenic regulation, membrane trafficking, and steroid responsiveness. The interrelationships between these functions are currently poorly understood. Previous work has shown that different MAPR subclasses were present early in eukaryotic evolution, and that tyrosine phosphorylated residues appeared in the eumetazoan ancestor, coincident with a gastrulation organizer. Here we show that MAPR proteins are related to a newly recognized class of prokaryotic cytochrome-b5 domain proteins. Our first solved structure of this new class exhibits shared MAPR-like folded architecture and heme-binding orientation. We also report that a protein subgroup from Candidate Phyla Radiation bacteria shares MAPR-like heme-interacting tyrosines. Our results support bacterial origins for both PGRMC1 and CYP51A, that catalyze the meiosis-associated 14-demethylation of the first sterol lanosterol from yeast to humans. We propose that eukaryotic acquisition of a membrane-trafficking function related to sterol metabolism was associated with the appearance of MAPR genes early in eukaryotic evolution.

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“…Further co-immunoprecipitation studies revealed a change in PGRMC1-associated proteins before and after decidualization. Strikingly, the vast majority of these proteins were implicated in endomembrane trafficking/cytoskeleton or mitochondrial function [ 159 , 160 ].…”

Section: Other Pgrmc1 Functions Found In Interphasic Cells Providing ...mentioning

confidence: 99%

“…As anticipated in the previous paragraph, PGRMC1 pull-down experiments were recently conducted in human ESCs to investigate the possible implication of PGRMC1 in the process of decidualization [ 159 , 160 ]. Notably, most of the PGRMC1-coprecipitated proteins were involved in endomembrane trafficking/cytoskeleton or mitochondrial functions, which links PGRMC1 to membrane trafficking, cytoskeletal remodeling, and cell shape.…”

Section: Other Pgrmc1 Functions Found In Interphasic Cells Providing ...mentioning

confidence: 99%

Insights on the Role of PGRMC1 in Mitotic and Meiotic Cell Division

Lodde

Barros

Terzaghi

et al. 2022

Cancers

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During mitosis, chromosome missegregation and cytokinesis defects have been recognized as hallmarks of cancer cells. Cytoskeletal elements composing the spindle and the contractile ring and their associated proteins play crucial roles in the faithful progression of mitotic cell division. The hypothesis that PGRMC1, most likely as a part of a yet-to-be-defined complex, is involved in the regulation of spindle function and, more broadly, the cytoskeletal machinery driving cell division is particularly appealing. Nevertheless, more than ten years after the preliminary observation that PGRMC1 changes its localization dynamically during meiotic and mitotic cell division, this field of research has remained a niche and needs to be fully explored. To encourage research in this fascinating field, in this review, we will recap the current knowledge on PGRMC1 function during mitotic and meiotic cell division, critically highlighting the strengths and limitations of the experimental approaches used so far. We will focus on known interacting partners as well as new putative associated proteins that have recently arisen in the literature and that might support current as well as new hypotheses of a role for PGRMC1 in specific spindle subcompartments, such as the centrosome, kinetochores, and the midzone/midbody.

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Choose your partners for the next dance: implied PGRMC1 roles in membrane trafficking and mitochondrial modulation

Cited by 7 publications

References 6 publications

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

MAPR origins reveal a new class of prokaryotic cytochrome b₅ proteins and possible role in eukaryogenesis

Insights on the Role of PGRMC1 in Mitotic and Meiotic Cell Division

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Choose your partners for the next dance: implied PGRMC1 roles in membrane trafficking and mitochondrial modulation

Cited by 7 publications

References 6 publications

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

MAPR origins reveal a new class of prokaryotic cytochrome b5 proteins and possible role in eukaryogenesis

Insights on the Role of PGRMC1 in Mitotic and Meiotic Cell Division

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MAPR origins reveal a new class of prokaryotic cytochrome b₅ proteins and possible role in eukaryogenesis