Dataset Information

Solution Behavior of the Intrinsically Disordered N-Terminal Domain of Retinoid X Receptor ? in the Context of the Full-Length Protein.

ABSTRACT: Retinoid X receptors (RXRs) are transcription factors with important functions in embryonic development, metabolic processes, differentiation, and apoptosis. A particular feature of RXRs is their ability to act as obligatory heterodimerization partners of class II nuclear receptors. At the same time, these receptors are also able to form homodimers that bind to direct repeat separated by one nucleotide hormone response elements. Since the discovery of RXRs, most of the studies focused on its ligand binding and DNA binding domains, while its N-terminal domain (NTD) harboring a ligand-independent activation function remained poorly characterized. Here, we investigated the solution properties of the NTD of RXR? alone and in the context of the full-length receptor using small-angle X-ray scattering and nuclear magnetic resonance spectroscopy. We report the solution structure of the full-length homodimeric RXR? on DNA and show that the NTD remains highly flexible within this complex.

SUBMITTER: Belorusova A

PROVIDER: S-EPMC4968620 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Publications

Solution Behavior of the Intrinsically Disordered N-Terminal Domain of Retinoid X Receptor α in the Context of the Full-Length Protein.

Belorusova Anna A Osz Judit J Petoukhov Maxim V MV Peluso-Iltis Carole C Kieffer Bruno B Svergun Dmitri I DI Rochel Natacha N

Biochemistry 20160315 12

Retinoid X receptors (RXRs) are transcription factors with important functions in embryonic development, metabolic processes, differentiation, and apoptosis. A particular feature of RXRs is their ability to act as obligatory heterodimerization partners of class II nuclear receptors. At the same time, these receptors are also able to form homodimers that bind to direct repeat separated by one nucleotide hormone response elements. Since the discovery of RXRs, most of the studies focused on its lig ...[more]

PMID: 26937780

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Project description:HP1γ, a non-histone chromatin protein, has elicited significant attention because of its role in gene silencing, elongation, splicing, DNA repair, cell growth, differentiation, and many other cancer-associated processes, including therapy resistance. These characteristics make it an ideal target for developing small drugs for both mechanistic experimentation and potential therapies. While high-resolution structures of the two globular regions of HP1γ, the chromo- and chromoshadow domains, have been solved, little is currently known about the conformational behavior of the full-length protein. Consequently, in the current study, we use threading, homology-based molecular modeling, molecular mechanics calculations, and molecular dynamics simulations to develop models that allow us to infer properties of full-length HP1γ at an atomic resolution level. HP1γ appears as an elongated molecule in which three Intrinsically Disordered Regions (IDRs, 1, 2, and 3) endow this protein with dynamic flexibility, intermolecular recognition properties, and the ability to integrate signals from various intracellular pathways. Our modeling also suggests that the dynamic flexibility imparted to HP1γ by the three IDRs is important for linking nucleosomes with PXVXL motif-containing proteins, in a chromatin environment. The importance of the IDRs in intermolecular recognition is illustrated by the building and study of both IDR2 HP1γ-importin-α and IDR1 and IDR2 HP1γ-DNA complexes. The ability of the three IDRs for integrating cell signals is demonstrated by combined linear motif analyses and molecular dynamics simulations showing that posttranslational modifications can generate a histone mimetic sequence within the IDR2 of HP1γ, which when bound by the chromodomain can lead to an autoinhibited state. Combined, these data underscore the importance of IDRs 1, 2, and 3 in defining the structural and dynamic properties of HP1γ, discoveries that have both mechanistic and potentially biomedical relevance.

Dataset Information

Solution Behavior of the Intrinsically Disordered N-Terminal Domain of Retinoid X Receptor ? in the Context of the Full-Length Protein.

Publications

Solution Behavior of the Intrinsically Disordered N-Terminal Domain of Retinoid X Receptor α in the Context of the Full-Length Protein.

Similar Datasets

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