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We recently reported that the membrane-associated progesterone receptor (MAPR) protein family (mammalian members: PGRMC1, PGRMC2, NEUFC and NENF) originated from a new class of prokaryotic cytochrome b 5 (cytb 5 ) domain proteins, called cytb 5M (MAPR-like). Relative to classical cytb 5 proteins, MAPR and ctyb 5M proteins shared unique sequence elements and a distinct heme-binding orientation at an approximately 90° rotation relative to classical cytb 5 , as demonstrated in the archetypal crystal structure of a cytb 5M protein (PDB accession number 6NZX). Here, we present the crystal structure of an archaeal cytb 5M domain (Methanococcoides burtonii WP_011499504.1, PDB:6VZ6). It exhibits similar heme binding to the 6NZX cytb 5M , supporting the deduction that MAPR-like heme orientation was inherited from the prokaryotic ancestor of the original eukaryotic MAPR gene., (© 2022 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The c-fos proto-oncogene was discovered by homology to transforming viral genes, leading to speculation that transforming viruses had captured a cellular gene involved in cell cycle control. Indeed overexpression of c-Fos protein led to deregulated growth control, and c-Fos was thought to be so critically involved in cell cycle control that transcriptional transrepression of its own promoter was interpreted as a negative feedback mechanism. However, recent findings render this conclusion improbable, Fos transrepression being most parsimoniously explained as transcriptional squelching imposed by artificially elevated levels of exogenous Fos protein.

The serum response element (SRE) contributes to transcriptional repression of the c-fos proto-oncogene. We show that the transcription factor SRF is able to repress SRE-dependent transcription, apparently by sequestering a co-activator. Only the DNA-binding core region is required for this SRE-dependent repression. Furthermore the phosphorylation status at potential casein kinase II sites within an N-terminal repression domain affects SRE-independent transcription. SRF may thus pleiotropically influence cellular transcription, representing a novel aspect of SRF function.

An important function of transcription factors may be to sequester coactivators or corepressors of transcription. In this manner transcription factors could regulate in trans the activity of promoters to which they do not bind. This may be of widespread significance as a mechanism to control cell cycle-dependent and differentiation-specific transcriptional activity within eukaryotic cells. Therefore squelching in vivo may be important than hitherto appreciated.