User:Dong Woo Chin/Sandbox-HIF

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Revision as of 04:25, 30 April 2009

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Contents 1 Structural Interaction of HIF-1α and pVHL 1.1 Background 1.2 Hydroxylation of Proline-564 1.3 Interaction between HIF-1α and pVHL 1.4 References

Structural Interaction of HIF-1α and pVHL

spinqualitylabelsall models PDB ID 1lqb Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
1lqb, resolution 2.00Å ()
Ligands:
Non-Standard Residues:
Structural annotation: Resources: CATH : 1Lqba00, 1Lqbb00, 1Lqbc01, 1Lqbc02 InterPro : Ipr000626, Ipr001232, Ipr011333, Ipr002714, Ipr011598, Ipr013655, Ipr000014, Ipr000700, Ipr001610, Ipr001321, Ipr014887, Ipr001092 Pfam : PF03931, PF01847 SCOP : d1lqba_, d1lqbb_, d1lqbc_ UniProt : Q15370, Q15369, P40337, Q16665
Functional annotation: Cellular component: nucleus cytoplasm membrane cytosol mitochondrion endoplasmic reticulum Biological process: protein complex assembly regulation of transcription, DNA-dependent transcription ubiquitin cycle RNA elongation from RNA polymerase II promoter protein modification process regulation of transcription from RNA polymerase II promoter cell cycle anti-apoptosis negative regulation of cell proliferation positive regulation of cell differentiation protein ubiquitination negative regulation of transcription from RNA polymerase II promoter cell morphogenesis response to stress negative regulation of cell cycle proteolysis protein stabilization homeostatic process signal transduction response to hypoxia transcription, DNA-dependent positive regulation of transcription regulation of transcription Molecular function: protein binding transcription elongation regulator activity transcription factor binding signal transducer activity transcription regulator activity histone acetyltransferase binding DNA binding RNA polymerase II transcription factor activity, enhancer binding transcription factor activity protein heterodimerization activity
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

Background

HIF (Hypoxia-inducible factor) is a necessary component for the regulation of oxygen in the human body. When a cell undergoes a state of hypoxia—low oxygen concentration—HIF starts a reaction chain in order to keep the cell from hypoxic damage, and allows it to recover back to normoxia. HIF-1 is a heterodimeric protein, composed of both an alpha (HIF-1α) and a beta subunit (HIF-1β) that interact and form the activated transcription factor during hypoxia. Under normal oxygen conditions HIF-1 is suppressed by many different regulating proteins, including prolyl hydroxylase-domain enzymes (PHDs) and the von Hippel-Lindau tumor suppressor protein (pVHL). These proteins stop HIF from being active and starting an unnecessary signal transduction pathway. Under the conditions where HIF -1is unnecessary, PHD hydroxylates a certain amino acid within the HIF-1α subunit, and pVHL binds to the hydroxylated amino acid, which leads to the ubiquitation and proteosomal degradation of the HIF-1α subunit.

Hydroxylation of Proline-564

In the presence of O2(Normoxia) and Iron, prolyl hydroxylase domain (PHD) enzymes are highly functional.Under normoxia, Pro564 of HIF-1α is hydroxylated to by PHD, which allows pVHL to bind the site.

Interaction between HIF-1α and pVHL

Hyp564 completes an elaborate network of hydrogen bonds, providing a chemical basis for efficient capture of HIF-1α after oxygen-dependent hydroxylation. The sites that are responsible for hydrogen bonding are N67, R69, L562, H2O, H115, S111, W117, and Hyp564 (in blue and red). The binding of pVHL to hydroxylated HIF-α directs a multiprotein ubiqutin ligase to mediate proteosomal degradation of the HIF-1α subunit. Thus, the loss of HIF-1α Prevents the activation of the transcription factor, HIF. W88, Y98, S111, H115, and W117 make the shape of pocket which complements precisely the up-pucker conformation of the hydroxyproline ring.

References

• Komatsu DE et al. 2007. Enhanced Bone Regeneration Associated With Decreased Apoptosis in Mice with Partial HIF-1α Deficiency. Journal of Bone and Mineral Research. 22(3):366-74.
• Smith TG et al. 2008. The human side of hypoxia-inducible factor. British Journal of Haematology. 141(3):325-34.
• Wan C et al. 2008. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci U S A 105(2):686-91.
• Shen X et al. 2009. Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. Journal of Orthopaedic Research. Epub.
• Hon WC et al. 2002. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 417(6892):975-8