Egl nine homolog 1

NameEgl nine homolog 1
Synonyms
  • 1.14.11.29
  • C1orf12
  • HIF-PH2
  • HIF-prolyl hydroxylase 2
  • HPH-2
  • Hypoxia-inducible factor prolyl hydroxylase 2
  • PHD2
  • Prolyl hydroxylase domain-containing protein 2
  • SM-20
Gene NameEGLN1
OrganismHuman
Amino acid sequence
>lcl|BSEQ0004351|Egl nine homolog 1
MANDSGGPGGPSPSERDRQYCELCGKMENLLRCSRCRSSFYCCKEHQRQDWKKHKLVCQG
SEGALGHGVGPHQHSGPAPPAAVPPPRAGAREPRKAAARRDNASGDAAKGKVKAKPPADP
AAAASPCRAAAGGQGSAVAAEAEPGKEEPPARSSLFQEKANLYPPSNTPGDALSPGGGLR
PNGQTKPLPALKLALEYIVPCMNKHGICVVDDFLGKETGQQIGDEVRALHDTGKFTDGQL
VSQKSDSSKDIRGDKITWIEGKEPGCETIGLLMSSMDDLIRHCNGKLGSYKINGRTKAMV
ACYPGNGTGYVRHVDNPNGDGRCVTCIYYLNKDWDAKVSGGILRIFPEGKAQFADIEPKF
DRLLFFWSDRRNPHEVQPAYATRYAITVWYFDADERARAKVKYLTGEKGVRVELNKPSDS
VGKDVF
Number of residues426
Molecular Weight46020.585
Theoretical pI8.66
GO Classification
Functions
  • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors
  • enzyme binding
  • L-ascorbic acid binding
  • peptidyl-proline dioxygenase activity
  • peptidyl-proline 4-dioxygenase activity
  • iron ion binding
Processes
  • oxygen homeostasis
  • peptidyl-proline hydroxylation to 4-hydroxy-L-proline
  • regulation of transcription from RNA polymerase II promoter in response to hypoxia
  • response to nitric oxide
  • response to hypoxia
  • ventricular septum morphogenesis
  • cellular response to hypoxia
  • regulation of angiogenesis
  • negative regulation of sequence-specific DNA binding transcription factor activity
  • heart trabecula formation
  • cardiac muscle tissue morphogenesis
  • labyrinthine layer development
  • negative regulation of cAMP catabolic process
  • negative regulation of cyclic-nucleotide phosphodiesterase activity
Components
  • nucleus
  • cytosol
  • cytoplasm
General FunctionPeptidyl-proline dioxygenase activity
Specific FunctionCellular 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. Target proteins are preferentially recognized via a LXXLAP motif.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID11345052
UniProtKB IDQ9GZT9
UniProtKB Entry NameEGLN1_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0011600|Egl nine homolog 1 (EGLN1)
ATGGCCAATGACAGCGGCGGGCCCGGCGGGCCGAGCCCGAGCGAGCGAGACCGGCAGTAC
TGCGAGCTGTGCGGGAAGATGGAGAACCTGCTGCGCTGCAGCCGCTGCCGCAGCTCCTTC
TACTGCTGCAAGGAGCACCAGCGTCAGGACTGGAAGAAGCACAAGCTCGTGTGCCAGGGC
AGCGAGGGCGCCCTCGGCCACGGAGTGGGCCCACACCAGCATTCCGGCCCCGCGCCGCCG
GCTGCAGTGCCGCCGCCCAGGGCCGGGGCCCGGGAGCCCAGGAAGGCAGCGGCGCGCCGG
GACAACGCCTCCGGGGACGCGGCCAAGGGAAAAGTAAAGGCCAAGCCCCCGGCCGACCCA
GCGGCGGCCGCGTCGCCGTGTCGTGCGGCCGCCGGCGGCCAGGGCTCGGCGGTGGCTGCC
GAAGCCGAGCCCGGCAAGGAGGAGCCGCCGGCCCGCTCATCGCTGTTCCAGGAGAAGGCG
AACCTGTACCCCCCAAGCAACACGCCCGGGGATGCGCTGAGCCCCGGCGGCGGCCTGCGG
CCCAACGGGCAGACGAAGCCCCTGCCGGCGCTGAAGCTGGCGCTCGAGTACATCGTGCCG
TGCATGAACAAGCACGGCATCTGTGTGGTGGACGACTTCCTCGGCAAGGAGACCGGACAG
CAGATCGGCGACGAGGTGCGCGCCCTGCACGACACCGGGAAGTTCACGGACGGGCAGCTG
GTCAGCCAGAAGAGTGACTCGTCCAAGGACATCCGAGGCGATAAGATCACCTGGATCGAG
GGCAAGGAGCCCGGCTGCGAAACCATTGGGCTGCTCATGAGCAGCATGGACGACCTGATA
CGCCACTGTAACGGGAAGCTGGGCAGCTACAAAATCAATGGCCGGACGAAAGCCATGGTT
GCTTGTTATCCGGGCAATGGAACGGGTTATGTACGTCATGTTGATAATCCAAATGGAGAT
GGAAGATGTGTGACATGTATATATTATCTTAATAAAGACTGGGATGCCAAGGTAAGTGGA
GGTATACTTCGAATTTTTCCAGAAGGCAAAGCCCAGTTTGCTGACATTGAACCCAAATTT
GATAGACTGCTGTTTTTCTGGTCTGACCGTCGCAACCCTCATGAAGTACAACCAGCATAT
GCTACAAGGTACGCAATAACTGTTTGGTATTTTGATGCAGATGAGAGAGCACGAGCTAAA
GTAAAATATCTAACAGGTGAAAAAGGTGTGAGGGTTGAACTCAATAAACCTTCAGATTCG
GTCGGTAAAGACGTCTTCTAG
GenBank Gene IDAF246631
GeneCard IDNot Available
GenAtlas IDEGLN1
HGNC IDHGNC:1232
Chromosome Location1
Locus1q42.1
References
  1. Dupuy D, Aubert I, Duperat VG, Petit J, Taine L, Stef M, Bloch B, Arveiler B: Mapping, characterization, and expression analysis of the SM-20 human homologue, c1orf12, and identification of a novel related gene, SCAND2. Genomics. 2000 Nov 1;69(3):348-54. 11056053
  2. Taylor MS: Characterization and comparative analysis of the EGLN gene family. Gene. 2001 Sep 5;275(1):125-32. 11574160
  3. Hirsila M, Koivunen P, Gunzler V, Kivirikko KI, Myllyharju J: Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem. 2003 Aug 15;278(33):30772-80. Epub 2003 Jun 3. 12788921
  4. Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I: The full-ORF clone resource of the German cDNA Consortium. BMC Genomics. 2007 Oct 31;8:399. 17974005
  5. Gregory SG, Barlow KF, McLay KE, Kaul R, Swarbreck D, Dunham A, Scott CE, Howe KL, Woodfine K, Spencer CC, Jones MC, Gillson C, Searle S, Zhou Y, Kokocinski F, McDonald L, Evans R, Phillips K, Atkinson A, Cooper R, Jones C, Hall RE, Andrews TD, Lloyd C, Ainscough R, Almeida JP, Ambrose KD, Anderson F, Andrew RW, Ashwell RI, Aubin K, Babbage AK, Bagguley CL, Bailey J, Beasley H, Bethel G, Bird CP, Bray-Allen S, Brown JY, Brown AJ, Buckley D, Burton J, Bye J, Carder C, Chapman JC, Clark SY, Clarke G, Clee C, Cobley V, Collier RE, Corby N, Coville GJ, Davies J, Deadman R, Dunn M, Earthrowl M, Ellington AG, Errington H, Frankish A, Frankland J, French L, Garner P, Garnett J, Gay L, Ghori MR, Gibson R, Gilby LM, Gillett W, Glithero RJ, Grafham DV, Griffiths C, Griffiths-Jones S, Grocock R, Hammond S, Harrison ES, Hart E, Haugen E, Heath PD, Holmes S, Holt K, Howden PJ, Hunt AR, Hunt SE, Hunter G, Isherwood J, James R, Johnson C, Johnson D, Joy A, Kay M, Kershaw JK, Kibukawa M, Kimberley AM, King A, Knights AJ, Lad H, Laird G, Lawlor S, Leongamornlert DA, Lloyd DM, Loveland J, Lovell J, Lush MJ, Lyne R, Martin S, Mashreghi-Mohammadi M, Matthews L, Matthews NS, McLaren S, Milne S, Mistry S, Moore MJ, Nickerson T, O'Dell CN, Oliver K, Palmeiri A, Palmer SA, Parker A, Patel D, Pearce AV, Peck AI, Pelan S, Phelps K, Phillimore BJ, Plumb R, Rajan J, Raymond C, Rouse G, Saenphimmachak C, Sehra HK, Sheridan E, Shownkeen R, Sims S, Skuce CD, Smith M, Steward C, Subramanian S, Sycamore N, Tracey A, Tromans A, Van Helmond Z, Wall M, Wallis JM, White S, Whitehead SL, Wilkinson JE, Willey DL, Williams H, Wilming L, Wray PW, Wu Z, Coulson A, Vaudin M, Sulston JE, Durbin R, Hubbard T, Wooster R, Dunham I, Carter NP, McVean G, Ross MT, Harrow J, Olson MV, Beck S, Rogers J, Bentley DR, Banerjee R, Bryant SP, Burford DC, Burrill WD, Clegg SM, Dhami P, Dovey O, Faulkner LM, Gribble SM, Langford CF, Pandian RD, Porter KM, Prigmore E: The DNA sequence and biological annotation of human chromosome 1. Nature. 2006 May 18;441(7091):315-21. 16710414
  6. Semenza GL: HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell. 2001 Oct 5;107(1):1-3. 11595178
  7. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ: C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43-54. 11595184
  8. Huang J, Zhao Q, Mooney SM, Lee FS: Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem. 2002 Oct 18;277(42):39792-800. Epub 2002 Aug 13. 12181324
  9. Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG Jr: Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13459-64. Epub 2002 Sep 26. 12351678
  10. Oehme F, Ellinghaus P, Kolkhof P, Smith TJ, Ramakrishnan S, Hutter J, Schramm M, Flamme I: Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun. 2002 Aug 16;296(2):343-9. 12163023
  11. Cioffi CL, Liu XQ, Kosinski PA, Garay M, Bowen BR: Differential regulation of HIF-1 alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells. Biochem Biophys Res Commun. 2003 Apr 11;303(3):947-53. 12670503
  12. Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Burgel T, Jelkmann W, Acker H, Fandrey J: Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci. 2003 Apr 1;116(Pt 7):1319-26. 12615973
  13. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM: Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004 Sep 10;279(37):38458-65. Epub 2004 Jul 7. 15247232
  14. Ozer A, Wu LC, Bruick RK: The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A. 2005 May 24;102(21):7481-6. Epub 2005 May 16. 15897452
  15. Flashman E, Bagg EA, Chowdhury R, Mecinovic J, Loenarz C, McDonough MA, Hewitson KS, Schofield CJ: Kinetic rationale for selectivity toward N- and C-terminal oxygen-dependent degradation domain substrates mediated by a loop region of hypoxia-inducible factor prolyl hydroxylases. J Biol Chem. 2008 Feb 15;283(7):3808-15. Epub 2007 Dec 5. 18063574
  16. Gauci S, Helbig AO, Slijper M, Krijgsveld J, Heck AJ, Mohammed S: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal Chem. 2009 Jun 1;81(11):4493-501. doi: 10.1021/ac9004309. 19413330
  17. Steinhoff A, Pientka FK, Mockel S, Kettelhake A, Hartmann E, Kohler M, Depping R: Cellular oxygen sensing: Importins and exportins are mediators of intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2. Biochem Biophys Res Commun. 2009 Oct 2;387(4):705-11. doi: 10.1016/j.bbrc.2009.07.090. Epub 2009 Jul 23. 19631610
  18. Yasumoto K, Kowata Y, Yoshida A, Torii S, Sogawa K: Role of the intracellular localization of HIF-prolyl hydroxylases. Biochim Biophys Acta. 2009 May;1793(5):792-7. doi: 10.1016/j.bbamcr.2009.01.014. Epub 2009 Feb 5. 19339211
  19. Furlow PW, Percy MJ, Sutherland S, Bierl C, McMullin MF, Master SR, Lappin TR, Lee FS: Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J Biol Chem. 2009 Apr 3;284(14):9050-8. doi: 10.1074/jbc.M808737200. Epub 2009 Feb 10. 19208626
  20. Flashman E, Hoffart LM, Hamed RB, Bollinger JM Jr, Krebs C, Schofield CJ: Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen. FEBS J. 2010 Oct;277(19):4089-99. doi: 10.1111/j.1742-4658.2010.07804.x. Epub 2010 Aug 31. 20840591
  21. Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, Lopez Herraez D, Brutsaert T, Parra EJ, Moore LG, Shriver MD: Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet. 2010 Sep 9;6(9):e1001116. doi: 10.1371/journal.pgen.1001116. 20838600
  22. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. 20068231
  23. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R: Genetic evidence for high-altitude adaptation in Tibet. Science. 2010 Jul 2;329(5987):72-5. doi: 10.1126/science.1189406. Epub 2010 May 13. 20466884
  24. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. 21269460
  25. Su Y, Loos M, Giese N, Metzen E, Buchler MW, Friess H, Kornberg A, Buchler P: Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. Cancer. 2012 Feb 15;118(4):960-72. doi: 10.1002/cncr.26344. Epub 2011 Jul 26. 21792862
  26. Foxler DE, Bridge KS, James V, Webb TM, Mee M, Wong SC, Feng Y, Constantin-Teodosiu D, Petursdottir TE, Bjornsson J, Ingvarsson S, Ratcliffe PJ, Longmore GD, Sharp TV: The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat Cell Biol. 2012 Jan 29;14(2):201-8. doi: 10.1038/ncb2424. 22286099
  27. Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi: 10.1073/pnas.1210303109. Epub 2012 Jul 18. 22814378
  28. Seo KS, Park JH, Heo JY, Jing K, Han J, Min KN, Kim C, Koh GY, Lim K, Kang GY, Uee Lee J, Yim YH, Shong M, Kwak TH, Kweon GR: SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation. Oncogene. 2015 Mar 12;34(11):1354-62. doi: 10.1038/onc.2014.76. Epub 2014 Mar 31. 24681946
  29. Kumar P, Gullberg U, Olsson I, Ajore R: Myeloid translocation gene-16 co-repressor promotes degradation of hypoxia-inducible factor 1. PLoS One. 2015 May 14;10(5):e0123725. doi: 10.1371/journal.pone.0123725. eCollection 2015. 25974097
  30. McDonough MA, Li V, Flashman E, Chowdhury R, Mohr C, Lienard BM, Zondlo J, Oldham NJ, Clifton IJ, Lewis J, McNeill LA, Kurzeja RJ, Hewitson KS, Yang E, Jordan S, Syed RS, Schofield CJ: Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9814-9. Epub 2006 Jun 16. 16782814
  31. Chowdhury R, McDonough MA, Mecinovic J, Loenarz C, Flashman E, Hewitson KS, Domene C, Schofield CJ: Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. Structure. 2009 Jul 15;17(7):981-9. doi: 10.1016/j.str.2009.06.002. 19604478
  32. Chowdhury R, Flashman E, Mecinovic J, Kramer HB, Kessler BM, Frapart YM, Boucher JL, Clifton IJ, McDonough MA, Schofield CJ: Studies on the reaction of nitric oxide with the hypoxia-inducible factor prolyl hydroxylase domain 2 (EGLN1). J Mol Biol. 2011 Jul 8;410(2):268-79. doi: 10.1016/j.jmb.2011.04.075. Epub 2011 May 13. 21601578
  33. Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, McMullin MF, Lee FS: A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):654-9. Epub 2006 Jan 9. 16407130
  34. Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS: A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood. 2007 Sep 15;110(6):2193-6. Epub 2007 Jun 19. 17579185
  35. Song D, Li LS, Arsenault PR, Tan Q, Bigham AW, Heaton-Johnson KJ, Master SR, Lee FS: Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing. J Biol Chem. 2014 May 23;289(21):14656-65. doi: 10.1074/jbc.M113.541227. Epub 2014 Apr 7. 24711448
  36. Lorenzo FR, Huff C, Myllymaki M, Olenchock B, Swierczek S, Tashi T, Gordeuk V, Wuren T, Ri-Li G, McClain DA, Khan TM, Koul PA, Guchhait P, Salama ME, Xing J, Semenza GL, Liberzon E, Wilson A, Simonson TS, Jorde LB, Kaelin WG Jr, Koivunen P, Prchal JT: A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet. 2014 Sep;46(9):951-6. doi: 10.1038/ng.3067. Epub 2014 Aug 17. 25129147