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 transcription...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2002-09, Vol.277 (37), p.33950-33956
Main Authors: Abdel-Hafiz, Hany, Takimoto, Glenn S., Tung, Lin, Horwitz, Kathryn B.
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Binding Sites
Humans
Receptors, Progesterone - chemistry
Receptors, Progesterone - physiology
Repressor Proteins - physiology
Structure-Activity Relationship
SUMO-1 Protein - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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,387IKEE, located in the N terminus upstream of AF1. Self-squelching does not involve this site. SUMO-1 binds PR covalently at 387IKEE, but only if the C-terminal, liganded, hormone-binding domain is also present. A single point K388R mutation within the 387IKEE 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M204573200