Intrinsic disorder in nuclear hormone receptors.
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.
Krasowski
Matthew D
MD
Department of Pathology, University of Pittsburgh, Scaife Hall S-737, 3550 Terrace Street Pittsburgh, Pennsylvania 15261, USA.
Reschly
Erica J
EJ
Ekins
Sean
S
D000818:Animals; D018360:Crystallography, X-Ray; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism
D018160:Receptors, Cytoplasmic and Nuclear