Differences in collagen prolyl 4-hydroxylase assembly between two Caenorhabditis nematode species despite high amino acid sequence identity of the enzyme subunits

Winter, Alan D.; Keskiaho, Katriina; Kukkola, Liisa; McCormack, Gillian; Félix, Marie‐Anne; Myllyharju, Johanna; Page, Antony P.

doi:10.1016/j.matbio.2007.01.008

Cited by 9 publications

(13 citation statements)

References 36 publications

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“…The assembly properties of the highly homologous C. briggsae PHY-1 and PHY-2 are similar to those of the corresponding C. elegans polypeptides with the exception that in the absence of PHY-1, C. briggsae PHY-2 assembles into an active (PHY-2) 2 /(PDI-2) 2 tetramer instead of a PHY-2/PDI-2 dimer (40). Combined disruption of phy-1 and phy-2 gene function leads to the absence of all cuticle C-P4H forms in the two Caenorhabditis species and results in an embryonic lethal phenotype (33,35,36,40). Disruption of the phy-2 gene alone produces no visible phenotype, since the enhanced assembly of the PHY-1/PDI-2 dimer can fully compensate for the lack of the mixed tetramer (33,35,36,40).…”

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confidence: 79%

“…The main C-P4H form in C. elegans is a PHY-1/PHY-2/(PDI-2) 2 mixed tetramer, but both C. elegans PHY polypeptides can also assemble into an active dimer with PDI-2, albeit much less effectively (36). The assembly properties of the highly homologous C. briggsae PHY-1 and PHY-2 are similar to those of the corresponding C. elegans polypeptides with the exception that in the absence of PHY-1, C. briggsae PHY-2 assembles into an active (PHY-2) 2 /(PDI-2) 2 tetramer instead of a PHY-2/PDI-2 dimer (40). Combined disruption of phy-1 and phy-2 gene function leads to the absence of all cuticle C-P4H forms in the two Caenorhabditis species and results in an embryonic lethal phenotype (33,35,36,40).…”

mentioning

confidence: 83%

“…Combined disruption of phy-1 and phy-2 gene function leads to the absence of all cuticle C-P4H forms in the two Caenorhabditis species and results in an embryonic lethal phenotype (33,35,36,40). Disruption of the phy-2 gene alone produces no visible phenotype, since the enhanced assembly of the PHY-1/PDI-2 dimer can fully compensate for the lack of the mixed tetramer (33,35,36,40). Inactivation of the C. elegans and C. briggsae phy-1 genes alone leads to abnormal cuticle formation and dumpy and small phenotypes, respectively (33)(34)(35)(36)40).…”

mentioning

confidence: 99%

“…Disruption of the phy-2 gene alone produces no visible phenotype, since the enhanced assembly of the PHY-1/PDI-2 dimer can fully compensate for the lack of the mixed tetramer (33,35,36,40). Inactivation of the C. elegans and C. briggsae phy-1 genes alone leads to abnormal cuticle formation and dumpy and small phenotypes, respectively (33)(34)(35)(36)40). Although enhanced assembly of the PHY-2/PDI-2 dimer and (PHY-2) 2 /(PDI-2) 2 tetramer occurs in phy-1 null C. elegans and C. briggsae, respectively, these C-P4H forms cannot fully compensate for the lack of the mixed tetramer and the PHY-1/PDI-2 dimer (36,40).…”

mentioning

confidence: 99%

“…Inactivation of the C. elegans and C. briggsae phy-1 genes alone leads to abnormal cuticle formation and dumpy and small phenotypes, respectively (33)(34)(35)(36)40). Although enhanced assembly of the PHY-2/PDI-2 dimer and (PHY-2) 2 /(PDI-2) 2 tetramer occurs in phy-1 null C. elegans and C. briggsae, respectively, these C-P4H forms cannot fully compensate for the lack of the mixed tetramer and the PHY-1/PDI-2 dimer (36,40). The recombinant C. elegans PHY-3 differs from PHY-1 and PHY-2 in that C-P4H activity is only generated when it is coexpressed with another C. elegans PDI isoform, PDI-1, but not with PDI-2 (37,38).…”

mentioning

confidence: 99%

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Characterization of a Novel Caenorhabditis elegans Prolyl 4-Hydroxylase with a Unique Substrate Specificity and Restricted Expression in the Pharynx and Excretory Duct

Keskiaho

Kukkola

Page

et al. 2008

Journal of Biological Chemistry

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Collagen prolyl 4-hydroxylases (C-P4Hs) have a critical role in collagen synthesis, since 4-hydroxyproline residues are necessary for folding of the triple-helical molecules. Vertebrate C-P4Hs are ␣ 2 ␤ 2 tetramers in which the ␤ subunit is identical to protein-disulfide isomerase (PDI). Three isoforms of the catalytic ␣ subunit, PHY-1, PHY-2, and PHY-3, have been characterized from Caenorhabditis elegans, PHY-1 and PHY-2 being responsible for the hydroxylation of cuticle collagens, whereas PHY-3 is predicted to be involved in collagen synthesis in early embryos. We have characterized transcripts of two additional C. elegans ␣ subunit-like genes, Y43F8B.4 and C14E2.4. Three transcripts were generated from Y43F8B.4, and a polypeptide encoded by one of them, named PHY-4.1, assembled into active (PHY-4.1) 2 /(PDI-2) 2 tetramers and PHY-4.1/PDI-2 dimers when coexpressed with C. elegans PDI-2 in insect cells. The C14E2.4 transcript was found to have a frameshift leading to the absence of codons for two residues critical for P4H catalytic activity. Thus, C. elegans has altogether four functional C-P4H ␣ subunits, PHY-1, PHY-2, PHY-3, and PHY-4.1. The tetramers and dimers containing recombinant PHY-4.1 had a distinct substrate specificity from the other C-P4Hs in that they hydroxylated poly(L-proline) and certain other proline-rich peptides, including ones that are expressed in the pharynx, in addition to collagen-like peptides. These data and the observed restricted expression of the phy-4.1 transcript and PHY-4.1 polypeptide in the pharyngeal gland cells and the excretory duct suggest that in addition to collagens, PHY-4.1 may hydroxylate additional proline-rich proteins in vivo. Two animal prolyl 4-hydroxylase (P4H)2 families are currently known that are functionally distinct, although they both belong to the 2-oxoglutarate-dependent dioxygenases and require Fe 2ϩ , 2-oxoglutarate, and molecular oxygen for catalysis (1-6). The collagen P4Hs (C-P4Hs), enzymes residing within the endoplasmic reticulum, catalyze the hydroxylation of proline residues in the -X-Pro-Gly-triplets in collagens (1-3). Vertebrates have at least 28 collagen types, encoded by 43 distinct genes (3, 7), and C-P4Hs have a vital role in the synthesis of all of them, since the 4-hydroxyproline residues formed are required for folding of the newly synthesized collagen polypeptide chains into stable triple-helical molecules (1-3). The other P4H family acts as an oxygen sensor by regulating the stability of the hypoxia-inducible transcription factor (HIF), an ␣␤ dimer (2, 4 -6). Under normoxic conditions, two specific proline residues in the HIF-␣ subunit are subject to hydroxylation by the HIF-P4Hs, which are located in the cytoplasm and nucleus, resulting in binding of the von Hippel-Lindau E3 ubiquitin ligase complex and rapid targeting of HIF-␣ for proteasomal degradation (2, 4 -6). In hypoxia, the activity of the HIFP4Hs is inhibited, so that HIF-␣ accumulates and forms an active dimer with HIF-␤, which induces the expression of various hypoxia-in...

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