2gut
From Proteopedia
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Solution structure of the trans-activation domain of the human co-activator ARC105
Overview
The sterol regulatory element binding protein (SREBP) family of, transcription activators are critical regulators of cholesterol and fatty, acid homeostasis. We previously demonstrated that human SREBPs bind the, CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit, activator-recruited co-factor (ARC)/Mediator co-activator complexes, through unknown mechanisms. Here we show that SREBPs use the, evolutionarily conserved ARC105 (also called MED15) subunit to activate, target genes. Structural analysis of the SREBP-binding domain in ARC105 by, NMR revealed a three-helix bundle with marked similarity to the CBP/p300, KIX domain. In contrast to SREBPs, the CREB and c-Myb activators do not, bind the ARC105 KIX domain, although they interact with the CBP KIX, domain, revealing a surprising specificity among structurally related, activator-binding domains. The Caenorhabditis elegans SREBP homologue, SBP-1 promotes fatty acid homeostasis by regulating the expression of, lipogenic enzymes. We found that, like SBP-1, the C. elegans ARC105, homologue MDT-15 is required for fatty acid homeostasis, and show that, both SBP-1 and MDT-15 control transcription of genes governing, desaturation of stearic acid to oleic acid. Notably, dietary addition of, oleic acid significantly rescued various defects of nematodes targeted, with RNA interference against sbp-1 and mdt-15, including impaired, intestinal fat storage, infertility, decreased size and slow locomotion, suggesting that regulation of oleic acid levels represents a, physiologically critical function of SBP-1 and MDT-15. Taken together, our, findings demonstrate that ARC105 is a key effector of SREBP-dependent gene, regulation and control of lipid homeostasis in metazoans.
About this Structure
2GUT is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis., Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, Macol C, Iyer L, Tjian R, van den Heuvel S, Hart AC, Wagner G, Naar AM, Nature. 2006 Aug 10;442(7103):700-4. Epub 2006 Jun 21. PMID:16799563
Page seeded by OCA on Fri Feb 15 17:29:04 2008
