1x0o

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Revision as of 17:51, 12 November 2007

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human ARNT C-terminal PAS domain

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a promiscuous, bHLH-PAS (Per-ARNT-Sim) protein that forms heterodimeric transcriptional, regulator complexes with several other bHLH-PAS subunits to control a, variety of biological pathways, some of which are centrally involved in, disease initiation and/or progression. One of these is the hypoxia, response pathway, which allows eukaryotic cells to respond to low oxygen, tension via the formation of a heterodimeric complex between ARNT and, another bHLH-PAS protein, the hypoxia-inducible factor alpha (HIF-alpha)., We have previously shown that the C-terminal PAS domains of an HIF-alpha, isoform (HIF-2alpha) and ARNT interact in vitro, and that mutations in the, solvent-exposed beta-sheet surface of the HIF-2alpha domain not only, disrupt this interaction, but also greatly attenuate the hypoxia response, in living cells. Here, we have solved the solution structure of the, corresponding PAS domain of ARNT and show that it utilizes a very similar, interface for the interaction with the HIF-2alpha PAS domain. We also show, that this domain self-associates in a concentration-dependent manner, and, that the interface used in this homodimeric complex is very similar to, that used in the formation of heterodimer. In addition, using, experimentally derived NMR restraints, we used the program HADDOCK to, calculate a low-resolution model of the complex formed in solution by, these two PAS domains, and confirm the validity of this model using, site-directed spin labeling to obtain long-range distance information in, solution. With this information, we propose a model for the mode of, multi-PAS domain interaction in bHLH-PAS transcriptional activation, complexes.

Disease

Known disease associated with this structure: Leukemia, acute myeloblastic OMIM:[126110]

About this Structure

1X0O is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization., Card PB, Erbel PJ, Gardner KH, J Mol Biol. 2005 Oct 28;353(3):664-77. Epub 2005 Sep 6. PMID:16181639

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