Structure and Expression of the Human Lysyl Hydroxylase Gene (PLOD): Introns 9 and 16 Contain Alu Sequences at the Sites of Recombination in Ehlers-Danlos Syndrome Type VI Patients

Heikkinen, Jari; Hautala, Timo; Kivirikko, Kari I.; Myllylä, Raili

doi:10.1006/geno.1994.1654

Cited by 46 publications

(28 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggestion is consistent with the known expression levels of the endogenous proteins in vivo. The KDEL-containing chaperones and folding enzymes are generally known as the most abundant proteins in the ER lumen, whereas LH is expressed at a much lower level in tissues and cells studied thus far (33). Thus, there is no need for a highly efficient retention/retrieval system for LH in the ER lumen.…”

Section: Discussionmentioning

confidence: 99%

A Single C-terminal Peptide Segment Mediates Both Membrane Association and Localization of Lysyl Hydroxylase in the Endoplasmic Reticulum

Suokas¹,

Myllylä²,

Kellokumpu³

2000

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Hydroxylation of lysyl residues is crucial for the unique glycosylation pattern found in collagens and for the mechanical strength of fully assembled extracellular collagen fibers. Hydroxylation is catalyzed in the lumen of the endoplasmic reticulum (ER) by a specific enzyme, lysyl hydroxylase (LH). The absence of the known ERspecific retrieval motifs in its primary structure and its association with the ER membranes in vivo have suggested that the enzyme is localized in the ER via a novel retention/retrieval mechanism. We have identified here a 40-amino acid C-terminal peptide segment of LH that is able to convert cathepsin D, normally a soluble lysosomal protease, into a membrane-associated protein.The same segment also markedly slows down the transport of the reporter protein from the ER into post-ER compartments, as assessed by our pulse-chase experiments. The retardation efficiency mediated by this Cterminal peptide segment is comparable with that of the intact LH but lower than that of the KDEL receptorbased retrieval mechanism. Within this 40-amino acid segment, the first 25 amino acids appear to be the most crucial ones in terms of membrane association and ER localization, because the last 15 C-terminal amino acids did not possess substantial retardation activity alone. Our findings thus define a short peptide segment very close to the extreme C terminus of LH as the only necessary determinant both for its membrane association and localization in the ER.

show abstract

Section: Discussionmentioning

confidence: 99%

A Single C-terminal Peptide Segment Mediates Both Membrane Association and Localization of Lysyl Hydroxylase in the Endoplasmic Reticulum

Suokas¹,

Myllylä²,

Kellokumpu³

2000

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mRNAs for lysyl hydroxylase 1 and 2 have been found to be expressed in a variety of human tissues (16,27). The highest expression levels of the isoenzyme 1 mRNA have been found in the liver and skeletal muscle (27), whereas those for isoenzyme 2 mRNA have been found in the pancreas, placenta, heart, and skeletal muscle (16). Northern hybridization with a cDNA probe for lysyl hydroxylase 3 indicated the presence of only a single mRNA of about 3.0 kb, which was expressed in a variety of tissues (Fig.…”

Section: Isolation Of Cdna Clones For Human Lysyl Hydroxylasementioning

confidence: 99%

Cloning and characterization of a third human lysyl hydroxylase isoform

Passoja

Rautavuoma

Ala‐Kokko

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Lysyl hydroxylase (EC 1.14.11.4), a homodimer, catalyzes the formation of hydroxylysine in collagens. Recently, an isoenzyme termed lysyl hydroxylase 2 has been cloned from human sources [M. Valtavaara, H. Papponen, A.-M. Pirttilä, K. Hiltunen, H. Helander and R. Myllylä (1997) J. Biol. Chem. 272, 6831-6834]. We report here on the cloning of a third human lysyl hydroxylase isoenzyme, termed lysyl hydroxylase 3. The cDNA clones encode a 738 amino acid polypeptide, including a signal peptide of 24 residues. The overall amino acid sequence identity between the processed human lysyl hydroxylase 3 and 1 polypeptides is 59%, and that between the processed lysyl hydroxylase 3 and 2 polypeptides is 57%, whereas the identity to the processed Caenorhabditis elegans polypeptide is only 45%. All four recently identified critical residues at the catalytic site, two histidines, one aspartate, and one arginine, are conserved in all these polypeptides. The mRNA for lysyl hydroxylase 3 was found to be expressed in a variety of tissues, but distinct differences appear to exist in the expression patterns of the three isoenzyme mRNAs. Recombinant lysyl hydroxylase 3 expressed in insect cells by means of a baculovirus vector was found to be more soluble than lysyl hydroxylase 1 expressed in the same cell type. No differences in catalytic properties were found between the recombinant lysyl hydroxylase 3 and 1 isoenzymes. Deficiency in lysyl hydroxylase 1 activity is known to cause the type VI variant of the Ehlers-Danlos syndrome, and it is therefore possible that deficiency in lysyl hydroxylase 3 activity may lead to some other variant of this syndrome or to some other heritable connective tissue disorder.

show abstract

“…In situ hybridization studies have shown that Alu sequences are localized predominantly to the gene-rich R (reverse) bands of metaphase chromosomes (Korenberg and Rykowski 1988), regions which are preferentially involved in homologous and nonhomologous chromosomal exchange processes (for review, see Morgan and Crossen 1977). A number of disease-associated genetic rearrangements and deletions involve Alu sequences: several Philadelphia chromosome BCR-ABL translocation breakpoints (Chen et al 1989a,b); an inversion-deletion in [3-globin (Glanzmann thrombasthemia; Li and Bray 1993); and intragenic deletions in lysyl hydroxylase (EhlersDanlos syndrome Type VI: Heikkinen et al 1994;Pousi et al 1994), low-density lipoprotein receptor (familial hypercholesteremia: Lehrman et al 1987), apolipoprotein B (hypobetalipoproteinemia: Huang et a1.1989), adenosine deaminase (ADA-SCID: Berkvens et al 1990), and complement component C1 (hereditary angioedema: Stoppa-Lyonnet et al 1990).…”

Section: Genome Research ~ 1043mentioning

confidence: 99%

Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.

Smith¹,

Lee²,

Szabo³

et al. 1996

Genome Res.

252

189

View full text Add to dashboard Cite

Over 100 distinct disease-associated mutations have been identified in the breast-ovarian cancer susceptibility gene BRCAI. Loss of the wild-type allele in >90% of tumors from patients with inherited BRCAI mutations indicates tumor suppressive function. The low incidence of somatic mutations suggests that BRCAI inactivation in sporadic tumors occurs by alternative mechanisms, such as interstitial chromosomal deletion or reduced transcription. To identify possible features of the BRCA1 genomic region that may contribute to chromosomal instability as well as potential transcriptional regulatory elements, a 117,143-bp DNA sequence encompassing BRCA1 was obtained by random sequencing of four cosmids identified from a human chromosome 17 specific library. The 24 exons of BRCAI span an 81-kb region that has an unusually high density of AJu repetitive DNA {41.5%), but relatively low density [4.8%) of other repetitive sequences. BRCAI intron lengths range in size from 403 bp to 9.2 kb and contain the intragenic microsatellite markers DI7S1323, DI7SI322, and DI7S855, which localize to introns 12, 19, and 20, respectively. In addition to BRCAI, the contig contains two complete genes: RhoT, a member of the rho family of GTP binding proteins, and VAT1, an abundant membrane protein of cholinergic synaptic vesicles. Partial sequences of the IAI-JB B-box protein pseudogene and lip JS, an interferon induced leucine zipper protein, reside within the contig. An L21 ribosomal protein pseudogene is embedded in BRCA1 intron 13. The order of genes on the chromosome is: centromere-lFP JS-VATI-P, hoT-BRCAI-IAI-JB-telomere.[The sequence data described in this paper have been submitted to GenBank under accession no. L78833.] Inherited mutations in the breast-ovarian cancer susceptibility gene, BRCA1 (Hall et al. 1990;Miki et al. 1994), confer a lifetime risk of breast cancer greater than 80% and an increased risk of ovarian cancer (Newman et al. 1988;Easton et al. 1993;Ford et al. 1994). Evidence for tumor suppressive function of BRCA1 derives from the high proportion (87%) of truncating germ-line mutations, which likely represent loss-of-function alterations (Castilla et

show abstract

Structure and Expression of the Human Lysyl Hydroxylase Gene (PLOD): Introns 9 and 16 Contain Alu Sequences at the Sites of Recombination in Ehlers-Danlos Syndrome Type VI Patients

Cited by 46 publications

References 0 publications

A Single C-terminal Peptide Segment Mediates Both Membrane Association and Localization of Lysyl Hydroxylase in the Endoplasmic Reticulum

A Single C-terminal Peptide Segment Mediates Both Membrane Association and Localization of Lysyl Hydroxylase in the Endoplasmic Reticulum

Cloning and characterization of a third human lysyl hydroxylase isoform

Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.

Contact Info

Product

Resources

About