Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1 alpha/ERR gamma complex

作者：Devarakonda Srikripa; Gupta Kushol; Chalmers Michael J; Hunt John F; Griffin Patrick R; Van Duyne Gregory D; Spiegelman Bruce M^*

来源：Proceedings of the National Academy of Sciences, 2011, 108(46): 18678-18683.

DOI：10.1073/pnas.1113813108

Peroxisome proliferator activated receptor (PPAR) gamma coactivator-1 alpha (PGC-1 alpha) 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-1 alpha 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-1 alpha and ERR gamma. PGC-1 alpha activation domain (PGC-1 alpha(2-220)) is intrinsically disordered with limited secondary and no defined tertiary structure. Complex formation with ERR. induces significant changes in the conformational mobility of both partners, highlighted by significant stabilization of the ligand binding domain (ERR gamma LBD) as determined by HDX (hydrogen/deuterium exchange) and an observed disorder-to-order transition in PGC-1 alpha(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 ERR gamma LBD, revealing a stable and compact binary complex. These data show that PGC-1 alpha(2-220) undergoes a large-scale conformational change when binding to the ERR gamma LBD, LBD, 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-1 alpha, favorable for assembly of an active transcriptional complex. These data also provide structural insight into the versatile coactivation profile of PGC-1 alpha and can readily be extended to understand other transcriptional coregulators.

• 出版日期2011-11-15