Functions of MAPR (Membrane-Associated Progesterone Receptor) Family Members As Heme/Steroid-Binding Proteins

Abstract

Progesterone receptor membrane component 1 (PGRMC1), PGRMC2, neudesin, and neuferricin all contain a cytochrome b5-like heme/steroid-binding domain and belong to the membrane-associated progesterone receptor (MAPR) family. Their amino acid sequences are well conserved among vertebrates, from humans to zebrafish. MAPR family genes are abundantly expressed in the central nervous system and exhibit neurotrophic effects in neural cells. During lipid metabolism, PGRMC1 regulates cholesterol synthesis, and neudesin plays a role in adipogenesis. Their bioactivities are dependent on the binding of heme to their cytochrome b5-like heme/steroid-binding domains. Conversely, it has been reported that the binding of steroids to MAPR family proteins induces biological responses that are unrelated to the nuclear steroid receptors. The interaction between PGRMC1 and progesterone promotes cell survival and damage resistance by progesterone. Moreover, MAPR family proteins exhibit a unique expression pattern in breast cancer, indicating the possibility of using MAPR family members as drug target in breast cancer. In this review, we summarize the identification, structure, and bioactivity of members of the MAPR family, and present an essential overview of the current understanding of their physiological roles.

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

“…In adult mice, neudesin was expressed preferentially in the CNS spinal cord but also in several peripheral tissues (Kimura et al, 2005(Kimura et al, , 2012. NMR studies suggested a similar structure with a potential heme-binding pocket (Han et al, 2012).…”

“…The four MAPR proteins PGRMC1, PGRMC2, neuferricin and neudesin share a homologous CYB5-like heme/steroidbinding domain but lack homology with the classical nuclear or membrane-bound steroid receptors (Mifsud and Bateman, 2002;Min et al, 2005;Kimura et al, 2012). Recent crystallographic analyses confirmed the hemoprotein nature of PGRMC1 with a special five-coordinated heme iron involving Tyr113, as opposed to the six-coordinated heme with two axial histidines in CYB5 (Min et al, 2005;Kaluka et al, 2015;Kabe et al, 2016).…”

“…PRGMC1 is predominantly expressed in mammalian liver and kidney but also found in steroidogenic and reproductive tissues, brain, breast, heart, lung, skeletal muscle, pancreas, and other organs (Gerdes et al, 1998;Kimura et al, 2012). Typically it is colocalized with CYPs in the smooth ER, but it has also been localized in the nucleus, cytoplasm, plasma membrane, and mitochondria (Kimura et al, 2012;Piel et al, 2016).…”

“…Apart from this, MAPRs interact with an increasing number of different proteins and are involved in a wide variety of cellular functions including cholesterol and steroid homeostasis, cell cycle regulation, cell migration, neurogenesis, autophagy, heme homeostasis and more that are only briefly mentioned but not the focus of this review. Readers interested in these aspects are referred to excellent reviews by others Ahmed et al, 2012;Kimura et al, 2012;Neubauer et al, 2013;Cahill et al, 2016;Hasegawa et al, 2016).…”

The evolutionary appearance of signaling motifs in PGRMC1

“…This may be because Neudesin and Neferricin are present in the luminal compartment and secreted extracellularly (2,3,(24)(25)(26)(27)(28), however the presence of some observed phosphorylation events suggests that the MAPR domain of these proteins may also be found in the cytoplasm. The detection of O-N-acetylgalactosamine (O-GalNAc) glycosylation does not necessarily imply an extracellular location for Neudesin, since 14% of O-GalNAc proteins are annotated with nuclear Gene Ontogeny (GO) assignments (29).…”