title: An additional function of the rough endoplasmic reticulum protein complex prolyl 3-hydroxylase 1·cartilage-associated protein·cyclophilin B: the CXXXC motif reveals disulfide isomerase activity in vitro.
abstract: Collagen biosynthesis occurs in the rough endoplasmic reticulum, and many molecular chaperones and folding enzymes are involved in this process. The folding mechanism of type I procollagen has been well characterized, and protein disulfide isomerase (PDI) has been suggested as a key player in the formation of the correct disulfide bonds in the noncollagenous carboxyl-terminal and amino-terminal propeptides. Prolyl 3-hydroxylase 1 (P3H1) forms a hetero-trimeric complex with cartilage-associated protein and cyclophilin B (CypB). This complex is a multifunctional complex acting as a prolyl 3-hydroxylase, a peptidyl prolyl cis-trans isomerase, and a molecular chaperone. Two major domains are predicted from the primary sequence of P3H1: an amino-terminal domain and a carboxyl-terminal domain corresponding to the 2-oxoglutarate- and iron-dependent dioxygenase domains similar to the α-subunit of prolyl 4-hydroxylase and lysyl hydroxylases. The amino-terminal domain contains four CXXXC sequence repeats. The primary sequence of cartilage-associated protein is homologous to the amino-terminal domain of P3H1 and also contains four CXXXC sequence repeats. However, the function of the CXXXC sequence repeats is not known. Several publications have reported that short peptides containing a CXC or a CXXC sequence show oxido-reductase activity similar to PDI in vitro. We hypothesize that CXXXC motifs have oxido-reductase activity similar to the CXXC motif in PDI. We have tested the enzyme activities on model substrates in vitro using a GCRALCG peptide and the P3H1 complex. Our results suggest that this complex could function as a disulfide isomerase in the rough endoplasmic reticulum.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University and Shriners Hospital for Children, Research Department, Portland, Oregon 97239.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Bächinger
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002645:Chickens; D021983:Cyclophilins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018870:Endoplasmic Reticulum, Rough / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D064828:Prolyl Hydroxylases; D019704:Protein Disulfide-Isomerases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C108053:CRTAP protein, human; C486354:Crtap protein, mouse; D016326:Extracellular Matrix Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D010455:Peptides; D011506:Proteins; D011509:Proteoglycans; C081786:cyclophilin B; D064828:Prolyl Hydroxylases; C485657:P3H1 protein, human; D021983:Cyclophilins; D019704:Protein Disulfide-Isomerases
keywords: Collagen; Collagen Biosynthesis; Disulfide; Endoplasmic Reticulum (ER); Oxidation-Reduction; Prolyl 3-Hydroxylase; Protein Isomerase
references.citation: Biochemistry. 1979 Jul 10;18(14):3089-97
references.pmid: 465457
references.citation: Matrix Biol. 2003 Mar;22(1):15-24
references.pmid: 12714038
references.citation: PLoS Genet. 2009 Dec;5(12):e1000750
references.pmid: 19997487
references.citation: J Biol Chem. 2010 May 28;285(22):17253-62
references.pmid: 20363744
references.citation: J Biol Chem. 1995 Aug 4;270(31):18323-8
references.pmid: 7629154
references.citation: J Biol Chem. 2009 Jun 26;284(26):17641-7
references.pmid: 19419969
references.citation: Clin Genet. 2012 Nov;82(5):453-9
references.pmid: 21955071
references.citation: Trends Genet. 2004 Jan;20(1):33-43
references.pmid: 14698617
references.citation: Biochemistry. 1997 Dec 2;36(48):14985-91
references.pmid: 9398223
references.citation: Mol Cell. 2012 Oct 12;48(1):39-51
references.pmid: 22981861
references.citation: J Invest Dermatol. 1975 Jul;65(1):85-92
references.pmid: 50387
references.citation: J Biol Chem. 2010 Nov 12;285(46):35551-7
references.pmid: 20801878
references.citation: J Biochem. 2002 Sep;132(3):451-5
references.pmid: 12204115
references.citation: Mol Biol Cell. 1996 Jul;7(7):1015-24
references.pmid: 8862517
references.citation: Biochemistry. 1993 Jul 6;32(26):6649-55
references.pmid: 8329391
references.citation: EMBO J. 1993 Apr;12(4):1587-95
references.pmid: 8385607
references.citation: Arch Biochem Biophys. 1973 Oct;158(2):478-84
references.pmid: 4592982
references.citation: Antioxid Redox Signal. 2006 May-Jun;8(5-6):813-22
references.pmid: 16771672
references.citation: Am J Hum Genet. 2009 Oct;85(4):521-7
references.pmid: 19781681
references.citation: Biochemistry. 1991 Jan 22;30(3):613-9
references.pmid: 1988050
references.citation: J Biol Chem. 2012 Jun 22;287(26):22253-65
references.pmid: 22556420
references.citation: J Biol Chem. 2001 Apr 6;276(14):11287-93
references.pmid: 11134056
references.citation: J Biol Chem. 2007 Jan 26;282(4):2512-9
references.pmid: 17135260
references.citation: Science. 1992 Sep 11;257(5076):1496-502
references.pmid: 1523409
references.citation: Biochem Biophys Res Commun. 1973 May 1;52(1):115-20
references.pmid: 4712181
references.citation: Biochem J. 1983 Jul 1;213(1):225-34
references.pmid: 6615424
references.citation: Cell. 2006 Jan 13;124(1):61-73
references.pmid: 16413482
references.citation: Cell Cycle. 2007 Jul 15;6(14):1675-81
references.pmid: 17630507
references.citation: Cell. 2005 Jul 1;121(7):1059-69
references.pmid: 15989955
references.citation: N Engl J Med. 2010 Feb 11;362(6):521-8
references.pmid: 20089953
references.citation: J Biol Chem. 1998 Apr 17;273(16):9637-43
references.pmid: 9545296
references.citation: Am J Med Genet. 1993 Jan 15;45(2):152-62
references.pmid: 8456797
references.citation: J Biol Chem. 2004 Feb 6;279(6):4604-11
references.pmid: 14627699
references.citation: Biochem J. 1983 Jul 1;213(1):235-43
references.pmid: 6615425
references.citation: Methods Enzymol. 1982;82 Pt A:245-304
references.pmid: 6210830
references.citation: J Biol Chem. 1975 Apr 10;250(7):2470-4
references.pmid: 164442
references.citation: J Biol Chem. 1991 Jan 15;266(2):1299-303
references.pmid: 1985948
references.citation: Calcif Tissue Int. 2013 Oct;93(4):338-47
references.pmid: 23508630
references.citation: J Biol Chem. 2011 Sep 16;286(37):32705-12
references.pmid: 21757736
references.citation: Eur J Hum Genet. 2009 Dec;17(12):1560-9
references.pmid: 19550437
references.citation: Hum Mol Genet. 2011 Apr 15;20(8):1595-609
references.pmid: 21282188
references.citation: Mol Cell. 2011 Feb 18;41(4):432-44
references.pmid: 21329881
references.citation: Eur J Biochem. 1978 Oct 16;90(3):605-13
references.pmid: 710450
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2997-3002
references.pmid: 9501204
references.citation: EMBO Rep. 2005 Jan;6(1):28-32
references.pmid: 15643448
references.citation: Cell. 2006 Oct 20;127(2):291-304
references.pmid: 17055431
references.citation: Trends Biochem Sci. 2003 Apr;28(4):170-3
references.pmid: 12713899
references.citation: Trends Biochem Sci. 2004 Jan;29(1):1-4
references.pmid: 14729324
references.citation: J Med Genet. 2009 Apr;46(4):233-41
references.pmid: 19088120
references.citation: J Biochem. 2002 Sep;132(3):401-7
references.pmid: 12204109
references.citation: Biochim Biophys Acta. 2004 Jun 1;1699(1-2):35-44
references.pmid: 15158710
references.citation: Chem Biol. 2002 Jun;9(6):731-40
references.pmid: 12079785
references.citation: Bioessays. 1999 Nov;21(11):932-9
references.pmid: 10517866
references.citation: J Cell Sci. 1997 Jun;110 ( Pt 12):1351-9
references.pmid: 9217321
references.citation: Chem Biol. 1999 Dec;6(12):871-9
references.pmid: 10631515
references.citation: Cell Stress Chaperones. 2005 Autumn;10(3):211-20
references.pmid: 16184766
references.citation: J Biol Chem. 2004 May 28;279(22):23615-21
references.pmid: 15044469
references.citation: Crit Rev Biochem Mol Biol. 2010 Apr;45(2):106-24
references.pmid: 20199358
references.citation: J Biol Chem. 1964 Oct;239:3445-52
references.pmid: 14245401
references.citation: Curr Biol. 2001 Jul 24;11(14):1114-8
references.pmid: 11509234
references.citation: Biochim Biophys Acta. 2013 Nov;1833(11):2479-91
references.pmid: 23602968
references.citation: Biochemistry. 1993 Jul 27;32(29):7488-95
references.pmid: 8338847
references.citation: Science. 2008 Jul 25;321(5888):569-72
references.pmid: 18653895
references.citation: FEBS J. 2012 Jul;279(13):2262-71
references.pmid: 22487145
references.citation: Biochim Biophys Acta. 2009 Jan;1793(1):33-41
references.pmid: 18672008
references.citation: Nat Genet. 2007 Mar;39(3):359-65
references.pmid: 17277775
references.citation: J Biol Chem. 2000 May 5;275(18):13213-8
references.pmid: 10788425
references.citation: Biochim Biophys Acta. 2009 Jan;1793(1):52-9
references.pmid: 18590776
references.citation: Antioxid Redox Signal. 2009 Nov;11(11):2807-50
references.pmid: 19476414
references.citation: Biochemistry. 2003 May 13;42(18):5387-94
references.pmid: 12731880
references.citation: Biochem Biophys Res Commun. 1973 May 1;52(1):106-14
references.pmid: 4576266
references.citation: Eur J Biochem. 1980 May;106(2):619-32
references.pmid: 7398630
references.citation: Trends Biochem Sci. 2003 Dec;28(12):655-62
references.pmid: 14659697
references.citation: Nat Rev Genet. 2009 Mar;10(3):173-83
references.pmid: 19204719
references.citation: Biochem J. 1991 Apr 15;275 ( Pt 2):335-9
references.pmid: 2025220
references.citation: PLoS One. 2012;7(5):e36809
references.pmid: 22615817
references.citation: Hum Mutat. 2008 Dec;29(12):1435-42
references.pmid: 18566967
references.citation: Antioxid Redox Signal. 2010 Jan;12(1):53-91
references.pmid: 19634988