2GUT

Solution structure of the trans-activation domain of the human co-activator ARC105

Summary for 2GUT

• Entry DOI: 10.2210/pdb2gut/pdb
• NMR Information: BMRB: 7185
• Descriptor: ARC/MEDIATOR, Positive cofactor 2 glutamine/Q-rich-associated protein (1 entity in total)
• Functional Keywords: kix, 3 helical bundle, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q96RN5
• Total number of polymer chains: 1
• Total formula weight: 8791.07

Authors

Vought, B.W.,Jim Sun, Z.-Y.,Hyberts, S.G.,Wagner, G.,Naar, A.M. (deposition date: 2006-05-01, release date: 2006-08-08, Last modification date: 2024-05-29)

Primary citation

Yang, F.,Vought, B.W.,Satterlee, J.S.,Walker, A.K.,Jim Sun, Z.-Y.,Watts, J.L.,Debeaumont, R.,Mako Saito, R.,Hyberts, S.G.,Yang, S.,Macol, C.,Iyer, L.,Tjian, R.,van den Heuvel, S.,Hart, A.C.,Wagner, G.,Naar, A.M.
An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis.
Nature, 442:700-704, 2006

PubMed Abstract: 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.

PubMed: 16799563
DOI: 10.1038/nature04942

Experimental method

SOLUTION NMR