Progesterone receptors (PR)-B and -A regulate transcription by different mechanisms: AF-3 exerts regulatory control over coactivator binding to PR-B.

The two, nearly identical, isoforms of human progesterone receptors (PR), PR-B and -A, share activation functions (AF) 1 and 2, yet they possess markedly different transcriptional profiles, with PR-B being much stronger transactivators. Their differences map to a unique AF3 in the B-upstream segment (BUS), at the far N terminus of PR-B, which is missing in PR-A. Combined mutation of two LXXLL motifs plus tryptophan 140 in BUS, to yield PR-BdL140, completely destroys PR-B activity, because strong AF3 synergism with downstream AF1 and AF2 is eliminated.

Functional properties of the N-terminal region of progesterone receptors and their mechanistic relationship to structure.

Progesterone receptors (PR) are present in two isoforms, PR-A and PR-B. The B-upstream segment (BUS) of PR-B is a 164 amino acid N-terminal extension that is missing in PR-A and is responsible for the functional differences reported between the two isoforms. BUS contains an activation function (AF3) which is defined by a core domain between residues 54-154 whose activity is dependent upon a single Trp residue and two LXXLL motifs.

The inhibitory function in human progesterone receptor N termini binds SUMO-1 protein to regulate autoinhibition and transrepression.

Although most studies of progesterone receptors (PR) and their two isoforms, PR-A and PR-B, focus on transcriptional stimulation, the receptors exhibit important inhibitory properties. Autoinhibition refers to an inhibitory function located in the PR N terminus, whose deletion increases transcriptional activity at least 6-10-fold. Transrepression refers to the ability of PR-A to suppress the transcriptional activity of PR-B and other nuclear receptors, including estrogen receptors.