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. Self-squelching refers to the observation in transient transfection assays that increasing receptor concentrations paradoxically decrease transcriptional activity. Using a series of N-terminal deletion mutants constructed in both PR isoforms, we have mapped their autoinhibitory and transrepressor activities to a small ubiquitin-like modifier (SUMO-1) protein consensus-binding motif, (387)IKEE, located in the N terminus upstream of AF1. Self-squelching does not involve this site. SUMO-1 binds PR covalently at (387)IKEE, but only if the C-terminal, liganded, hormone-binding domain is also present. A single point K388R mutation within the (387)IKEE motif in either PR-A or PR-B leads to a loss of autoinhibitory and transrepressor functions of the liganded, full-length receptors. We conclude that autoinhibition and transrepression involve N-terminal sumoylation combined with intramolecular N/C-terminal communication.
Department of Medicine, Molecular Biology Program, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA. hany.abdel-hafiz@uchsc.edu
Hany
H
Abdel-Hafiz
Glenn S
GS
Takimoto
Lin
L
Tung
Kathryn B
KB
Horwitz
D020816:Amino Acid Motifs; D001665:Binding Sites; D006801:Humans; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D025842:SUMO-1 Protein / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011980:Receptors, Progesterone; D012097:Repressor Proteins; D025842:SUMO-1 Protein