User:Dong Woo Chin/Sandbox-HIF
From Proteopedia
Contents |
Structural Interaction of HIF-1α and pVHL
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 (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 These proteins stop HIF from being active and starting an unnecessary signal transduction pathway. Under the conditions where HIF -1 is 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. Peet Lab from the University of Adelaide explains this pathway in detail.
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. . W88, Y98, S111, H115, and W117 make the shape of pocket which “complements precisely the up-pucker conformation of the hydroxyproline ring.” 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-1.
Bone Regeneration and HIF-1α
A 2007 experiment (Komatsu et al) explored HIF-1α’s involvement in bone regeneration. The experimenters differentiated utilized wild type HIF-1α+/+ and partially deficient HIF-1α+/-mice and compared femoral healing rates. The findings discovered that the HIF-1α partial deficiency enhances bone regeneration. However, promoted HIF-1α expression level by deletion of pVHL or by PHD inhibition improved bone regeneration and increased callus formation in mice. (Wan C et al, 2008 and Shen X et al, 2009) The conclusions from these studies are contrary to the findings of the previous study done by Komatsu et al.
References
- Hon WC et al. 2002. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 417(6892):975-8
- 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.
- Shen X et al. 2009. Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. Journal of Orthopaedic Research. Epub.
- 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.
