INTRINSIC DISORDER IN NUCLEAR HORMONE RECEPTORS

Matthew D Krasowski; Erica J Reschly; Sean Ekins

doi:10.1021/pr8003024

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INTRINSIC DISORDER IN NUCLEAR HORMONE RECEPTORS

Journal article

Open access

Peer reviewed

INTRINSIC DISORDER IN NUCLEAR HORMONE RECEPTORS

Matthew D Krasowski, Erica J Reschly and Sean Ekins

Journal of proteome research, Vol.7(10), pp.4359-4372

10/2008

DOI: 10.1021/pr8003024

PMCID: PMC2700763

PMID: 18651760

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https://www.ncbi.nlm.nih.gov/pmc/articles/2700763View

Open Access

Abstract

Many proteins possess intrinsic disorder (ID) and lack a rigid three-dimensional structure in at least part of their sequence. ID has been hypothesized to influence protein-protein and protein-ligand interactions. We calculated ID for nearly 400 vertebrate and invertebrate members of the biomedically important nuclear hormone receptor (NHR) superfamily, including all 48 known human NHRs. The predictions correctly identified regions in 20 of the 23 NHRs suggested as disordered based on published X-ray and NMR structures. Of the four major NHR domains (N-terminal domain, DNA-binding domain, D-domain, and ligand-binding domain), we found ID to be highest in the D-domain, a region of NHRs critical in DNA recognition and heterodimerization, coactivator/corepressor interactions and protein-protein interactions. ID in the D-domain and LBD was significantly higher in “hub” human NHRs that have 10 or more downstream proteins in their interaction networks compared to “non-hub” NHRs that interact with fewer than 10 downstream proteins. ID in the D-domain and LBD was also higher in classic, ligand-activated NHRs than in orphan, ligand-independent NHRs in human. The correlation between ID in human and mouse NHRs was high. Less correlation was found for ID between mammalian and non-mammalian vertebrate NHRs. For some invertebrate species, particularly sea squirts ( Ciona ), marked differences were observed in ID between invertebrate NHRs and their vertebrate orthologs. Our results indicate that variability of ID within NHRs, particularly in the D-domain and LBD, is likely an important evolutionary force in shaping protein-protein interactions and NHR function. This information enables further understanding of these therapeutic targets.

Ingenuity Pathways Analysis

D-domain

PONDR

ligand-protein interactions

nuclear hormone receptor

intrinsic disorder

orphan receptor

X-ray structure

ligand binding domain

protein-protein interactions

Details

Title: Subtitle: INTRINSIC DISORDER IN NUCLEAR HORMONE RECEPTORS
Creators: Matthew D Krasowski - Department of Pathology, University of Pittsburgh, Scaife Hall S-737, 3550 Terrace Street Pittsburgh, Pennsylvania 15261
Erica J Reschly - Department of Pathology, University of Pittsburgh, Scaife Hall S-737, 3550 Terrace Street Pittsburgh, Pennsylvania 15261
Sean Ekins - Collaborations in Chemistry, Inc., Jenkintown, Pennsylvania 19046
Resource Type: Journal article
Publication Details: Journal of proteome research, Vol.7(10), pp.4359-4372
DOI: 10.1021/pr8003024
PMID: 18651760
PMCID: PMC2700763
NLM abbreviation: J Proteome Res
ISSN: 1535-3893
eISSN: 1535-3907
Language: English
Date published: 10/2008
Academic Unit: Pathology
Record Identifier: 9984047645002771

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