Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response. Export

@article{citeulike:1907531, abstract = {The cellular response to low tissue oxygen concentrations is mediated by the hypoxia-inducible transcription factor HIF-1. Under hypoxic conditions, HIF-1 activates transcription of critical adaptive genes by recruitment of the general coactivators CBP/p300 through interactions with its alpha-subunit (Hif-1 alpha). Disruption of the Hif-1 alpha/p300 interaction has been linked to attenuation of tumor growth. To delineate the structural basis for this interaction, we have determined the solution structure of the complex between the carboxy-terminal activation domain (CAD) of Hif-1 alpha and the zinc-binding TAZ1 (CH1) motif of cyclic-AMP response element binding protein (CREB) binding protein (CBP). Despite the overall similarity of the TAZ1 structure to that of the TAZ2 (part of the CH3) domain of CBP, differences occur in the packing of helices that can account for differences in specificity. The unbound CAD is intrinsically disordered and remains relatively extended upon binding, wrapping almost entirely around the TAZ1 domain in a groove through much of its surface. Three short helices are formed upon binding, stabilized by intermolecular interactions. The Asn-803 side chain, which functions as a hypoxic switch, is located on the second of these helices and is buried in the molecular interface. The third helix of the Hif-1 alpha CAD docks in a deep hydrophobic groove in TAZ1, providing extensive intermolecular hydrophobic interactions that contribute to the stability of the complex. The structure of this complex provides new insights into the mechanism through which Hif-1 alpha recruits CBP/p300 in response to hypoxia.}, address = {Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.}, author = {Dames, S. A. and Martinez-Yamout, M. and De Guzman, R. N. and Dyson, H. J. and Wright, P. E.}, citeulike-article-id = {1907531}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.082121399}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/11959977}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=11959977}, day = {16}, doi = {10.1073/pnas.082121399}, issn = {0027-8424}, journal = {Proc Natl Acad Sci U S A}, keywords = {ch1, hif-1a, kix, nmr-structure}, month = {April}, number = {8}, pages = {5271--5276}, posted-at = {2008-07-21 17:07:36}, priority = {2}, title = {Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response.}, url = {http://dx.doi.org/10.1073/pnas.082121399}, volume = {99}, year = {2002} }

TY - JOUR ID - citeulike:1907531 L3 - citeulike-article-id:1907531 N2 - The cellular response to low tissue oxygen concentrations is mediated by the hypoxia-inducible transcription factor HIF-1. Under hypoxic conditions, HIF-1 activates transcription of critical adaptive genes by recruitment of the general coactivators CBP/p300 through interactions with its alpha-subunit (Hif-1 alpha). Disruption of the Hif-1 alpha/p300 interaction has been linked to attenuation of tumor growth. To delineate the structural basis for this interaction, we have determined the solution structure of the complex between the carboxy-terminal activation domain (CAD) of Hif-1 alpha and the zinc-binding TAZ1 (CH1) motif of cyclic-AMP response element binding protein (CREB) binding protein (CBP). Despite the overall similarity of the TAZ1 structure to that of the TAZ2 (part of the CH3) domain of CBP, differences occur in the packing of helices that can account for differences in specificity. The unbound CAD is intrinsically disordered and remains relatively extended upon binding, wrapping almost entirely around the TAZ1 domain in a groove through much of its surface. Three short helices are formed upon binding, stabilized by intermolecular interactions. The Asn-803 side chain, which functions as a hypoxic switch, is located on the second of these helices and is buried in the molecular interface. The third helix of the Hif-1 alpha CAD docks in a deep hydrophobic groove in TAZ1, providing extensive intermolecular hydrophobic interactions that contribute to the stability of the complex. The structure of this complex provides new insights into the mechanism through which Hif-1 alpha recruits CBP/p300 in response to hypoxia. IS - 8 JF - Proc Natl Acad Sci U S A SN - 0027-8424 AD - Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. EP - 5276 TI - Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response. VL - 99 SP - 5271 KW - ch1 KW - hif-1a KW - kix KW - nmr-structure AU - Dames, SA AU - Martinez-Yamout, M AU - De Guzman, RN AU - Dyson, HJ AU - Wright, PE PY - 2002/04/16/ UR - http://dx.doi.org/10.1073/pnas.082121399 ER -