Structural basis for PAS domain heterodimerization in the basic helix-loop-helix-PAS transcription factor hypoxia-inducible factor

被引:195
作者
Erbel, PJA
Card, PB
Karakuzu, O
Bruick, RK
Gardner, KH
机构
[1] Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA
关键词
D O I
10.1073/pnas.2533374100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Biological responses to oxygen availability play important roles in development, physiological homeostasis, and many disease processes. In mammalian cells, this adaptation is mediated in part by a conserved pathway centered on the hypoxia-inducible factor (HIF). HIF is a heterodimeric protein complex composed of two members of the basic helix-loop-helix Per-ARNT-Sim (PAS) (ARNT, aryl hydrocarbon receptor nuclear translocator) domain family of transcriptional activators, HIFalpha and ARNT. Although this complex involves protein-protein interactions mediated by basic helix-loop-helix and PAS domains in both proteins, the role played by the PAS domains is poorly understood. To address this issue, we have studied the structure and interactions of the C-terminal PAS domain of human HIF-2alpha by NMR spectroscopy. We demonstrate that HIF-2alpha PAS-beta binds the analogous ARNT domain in vitro, showing that residues involved in this interaction are located on the solvent-exposed side of the HIF-2alpha central beta-sheet. Mutating residues at this surface not only disrupts the interaction between isolated PAS domains in vitro but also interferes with the ability of full-length HIF to respond to hypoxia in living cells. Extending our findings to other PAS domains, we find that this beta-sheet interface is widely used for both intra- and intermolecular interactions, suggesting a basis of specificity and regulation of many types of PAS-containing signaling proteins.
引用
收藏
页码:15504 / 15509
页数:6
相关论文
共 43 条
  • [1] Structure and interactions of PAS kinase N-terminal PAS domain: Model for intramolecular kinase regulation
    Amezcua, CA
    Harper, SM
    Rutter, J
    Gardner, KH
    [J]. STRUCTURE, 2002, 10 (10) : 1349 - 1361
  • [2] PRIMARY STRUCTURE EFFECTS ON PEPTIDE GROUP HYDROGEN-EXCHANGE
    BAI, YW
    MILNE, JS
    MAYNE, L
    ENGLANDER, SW
    [J]. PROTEINS-STRUCTURE FUNCTION AND GENETICS, 1993, 17 (01): : 75 - 86
  • [3] 1.4 ANGSTROM STRUCTURE OF PHOTOACTIVE YELLOW PROTEIN, A CYTOSOLIC PHOTORECEPTOR - UNUSUAL FOLD, ACTIVE-SITE, AND CHROMOPHORE
    BORGSTAHL, GEO
    WILLIAMS, DR
    GETZOFF, ED
    [J]. BIOCHEMISTRY, 1995, 34 (19) : 6278 - 6287
  • [4] Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia
    Bruick, RK
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (16) : 9082 - 9087
  • [5] Crystallography & NMR system:: A new software suite for macromolecular structure determination
    Brunger, AT
    Adams, PD
    Clore, GM
    DeLano, WL
    Gros, P
    Grosse-Kunstleve, RW
    Jiang, JS
    Kuszewski, J
    Nilges, M
    Pannu, NS
    Read, RJ
    Rice, LM
    Simonson, T
    Warren, GL
    [J]. ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 : 905 - 921
  • [6] Crystal structure and functional analysis of the HERG potassium channel N terminus: A eukaryotic PAS domain
    Cabral, JHM
    Lee, A
    Cohen, SL
    Chait, BT
    Li, M
    Mackinnon, R
    [J]. CELL, 1998, 95 (05) : 649 - 655
  • [7] Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation
    Chen, J
    Zou, AR
    Splawski, I
    Keating, MT
    Sanguinetti, MC
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (15) : 10113 - 10118
  • [8] Structure of a flavin-binding plant photoreceptor domain: Insights into light-mediated signal transduction
    Crosson, S
    Moffat, K
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (06) : 2995 - 3000
  • [9] Photoactive yellow protein: A prototypic PAS domain sensory protein and development of a common signaling mechanism
    Cusanovich, MA
    Meyer, TE
    [J]. BIOCHEMISTRY, 2003, 42 (17) : 4759 - 4770
  • [10] High-throughput NMR-based screening with competition binding experiments
    Dalvit, C
    Flocco, M
    Knapp, S
    Mostardini, M
    Perego, R
    Stockman, BJ
    Veronesi, M
    Varasi, M
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124 (26) : 7702 - 7709