A model for the complex between the hypoxia-inducible factor-1 (HIF-1) andits consensus DNA sequence

Citation
G. Michel et al., A model for the complex between the hypoxia-inducible factor-1 (HIF-1) andits consensus DNA sequence, J BIO STRUC, 18(2), 2000, pp. 169-179
Citations number
28
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
ISSN journal
07391102 → ACNP
Volume
18
Issue
2
Year of publication
2000
Pages
169 - 179
Database
ISI
SICI code
0739-1102(200010)18:2<169:AMFTCB>2.0.ZU;2-0
Abstract
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor activated by hypoxia. When activated, HIF-1 mediates the differential expre ssion of genes such as erythropoietin and Vascular Endothelial Growth Facto r (VEGF) during hypoxia. It is composed of two different subunits, HIF-1 al pha and ARNT (Aryl Receptor Nuclear Translocator). These two subunits belon g to the bHLH (basic Helix-Loop-Helix) PAS (Per, Ahr/ARNT, Sim) family. The bHLH domain of these factors is responsible for dimerization through the t wo helices and for DNA binding through their basic domain. In this work, we used various methods of molecular modeling in order to dev elop a 3D structure for the HIF-1 bHLH domain bound to its DNA consensus se quence. Firstly, the 3D structure of the bHLH domain of both subunits based on their amino acid sequence was defined. Secondly, we compared this model with data from known crystal structures of basic leucine zipper-DNA and bH LH-DNA complexes in order to determine a potential canvas for HIF-1. Thirdl y, we performed a manual approach of the HF-1 bHLH domain onto the DNA reco gnition site using this canvas. Finally, the protein-DNA complex 3D structu re was optimized using a Monte Carlo program called MONTY. The model predicted a pattern of interactions between amino acids and DNA b ases which reflect for ARNT what is experimentally observed among different X-ray structures of other bHLH transcription factors possessing the H (His ), E (Glu), R (Arg) triad, as ARNT does. On the other hand, only the Arg re sidue is conserved in HIF-1 alpha. We propose from this model that a serine replaces the histidine while an alanine and a lysine also make contacts wi th DNA. From these results, we postulate that the specificity of HIF-1 towa rd its DNA sequence could be driven by the HIF-1 alpha subunit. The predict ed model will be verified by X-Ray currently ongoing.