Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1α/ERRγ complex
Year: 2011
Type: article
Abstract: Peroxisome proliferator activated receptor (PPAR) γ coactivator-1α (PGC-1α) is a potent transcriptional coactivator of oxidative metabolism and is induced in response to a variety of environmental cues. It regulates a broad array of target genes by coactivating a whole host of transcription factors. The estrogen-related receptor (ERR) family of nuclear receptors are key PGC-1α partners in the regulation of mitochondrial and tissue-specific oxidative metabolic pathways; these receptors also demonstrate strong physical and functional interactions with this coactivator. Here we perform comprehensive biochemical, biophysical, and structural analyses of the complex formed between PGC-1α and ERRγ. PGC-1α activation domain (PGC-1α(2-220)) is intrinsically disordered with limited secondary and no defined tertiary structure. Complex formation with ERRγ induces significant changes in the conformational mobility of both partners, highlighted by significant stabilization of the ligand binding domain (ERRγLBD) as determined by HDX (hydrogen/deuterium exchange) and an observed disorder-to-order transition in PGC-1α(2-220). Small-angle X-ray scattering studies allow for modeling of the solution structure of the activation domain in the absence and presence of ERRγLBD, revealing a stable and compact binary complex. These data show that PGC-1α(2-220) undergoes a large-scale conformational change when binding to the ERRγLBD, leading to substantial compaction of the activation domain. This change results in stable positioning of the N-terminal part of the activation domain of PGC-1α, favorable for assembly of an active transcriptional complex. These data also provide structural insight into the versatile coactivation profile of PGC-1α and can readily be extended to understand other transcriptional coregulators.
Authors: Srikripa Devarakonda, Kushol Gupta, Michael J. Chalmers, John F. Hunt, Patrick R. Griffin, Gregory D. Van Duyne, Bruce M. Spiegelman
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: The Comprehensive Center for Chemical Probe Discovery and Optimization at Scripps, Structural Genomics of Eukaryotic Domain Families, Macromolecular Diffraction Resource: MacCHESS, Structural Genomics of Eukaryotic Domain Families, Acquisition of a LTQ/Orbitrap MS to advance the study of protein dynamics, PGC1 proteins, meteorin-like and energy homeostasis, PGC1alpha and Irisin in the Control of Diabetes and Obesity, Development of H/D exchange technology for the study of large protein complexes
OpenAlex ID: W2087262569