5l9b
From Proteopedia
HIF PROLYL HYDROXYLASE 2 (PHD2/ EGLN1) IN COMPLEX WITH 2-OXOGLUTARATE (2OG) AND HIF-1ALPHA CODD (556-574)
Structural highlights
Disease[EGLN1_HUMAN] Defects in EGLN1 are the cause of familial erythrocytosis type 3 (ECYT3) [MIM:609820]. ECYT3 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels.[1] [2] Function[EGLN1_HUMAN] Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality.[3] [4] [5] [6] [7] [HIF1A_HUMAN] Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBPB and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia.[8] [9] [10] [11] [12] [13] [14] [15] [16] Publication Abstract from PubMedThe response to hypoxia in animals involves the expression of multiple genes regulated by the alphabeta-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFalpha isoforms, as catalysed by prolyl hydroxylases (PHD 1-3). Prolyl hydroxylation promotes binding of HIFalpha to the von Hippel-Lindau protein (VHL)-elongin B/C complex, thus signalling for proteosomal degradation of HIFalpha. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors. Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases.,Chowdhury R, Leung IK, Tian YM, Abboud MI, Ge W, Domene C, Cantrelle FX, Landrieu I, Hardy AP, Pugh CW, Ratcliffe PJ, Claridge TD, Schofield CJ Nat Commun. 2016 Aug 26;7:12673. doi: 10.1038/ncomms12673. PMID:27561929[17] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Hypoxia-inducible factor-proline dioxygenase | Chowdhury, R | Schofield, C J | 2-oxoglutarate | Beta-hydroxylation | Breast cancer | Cell structure | Cytoplasm | Development | Dna-binding | Dsbh | Egln1 | Facial triad | Familial erythrocytosis | Helix-loop-helix-beta | Hif | Hif prolyl hydroxylase domain 2 | Hypoxia | Hypoxia-inducible factor | Iron | Metal-binding | Non-heme dioxygenase | Oxidoreductase | Oxygenase | Phd2 | Polymorphism | Signaling | Transcription | Transcription activator/inhibitor | Transcription complex | Transcription/epigenetic regulation | Ubl conjugation | Vitamin c | Zinc-finger
