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J Cell Biol. 1992 January 2; 116(2): 559–571.
PMCID: PMC2289301

Human basement membrane heparan sulfate proteoglycan core protein: a 467-kD protein containing multiple domains resembling elements of the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor

Abstract

The primary structure of the large human basement membrane heparan sulfate proteoglycan (HSPG) core protein was determined from cDNA clones. The cDNA sequence codes for a 467-kD protein with a 21-residue signal peptide. Analysis of the amino acid sequence showed that the protein consists of five domains. The amino-terminal domain I contains three putative heparan sulfate attachment sites; domain II has four LDL receptor-like repeats; domain III contains repeats similar to those in the short arms of laminin; domain IV has lg-like repeats resembling those in neural cell adhesion molecules; and domain V contains sequences resembling repeats in the G domain of the laminin A chain and repeats in the EGF. The domain structure of the human basement membrane HSPG core protein suggests that this mosaic protein has evolved through shuffling of at least four different functional elements previously identified in other proteins and through duplication of these elements to form the functional domains. Comparison of the human amino acid sequence with a partial amino acid sequence from the corresponding mouse protein (Noonan, D. M., E. A. Horigan, S. R. Ledbetter, G. Vogeli, M. Sasaki, Y. Yamada, and J. R. Hassell. 1988. J. Biol. Chem. 263:16379-16387) shows a major difference between the species in domain IV, which contains the Ig repeats: seven additional repeats are found in the human protein inserted in the middle of the second repeat in the mouse sequence. This suggests either alternative splicing or a very recent duplication event in evolution. The multidomain structure of the basement membrane HSPG implies a versatile role for this protein. The heparan sulfate chains presumably participate in the selective permeability of basement membranes and, additionally, the core protein may be involved in a number of biological functions such as cell binding, LDL-metabolism, basement membrane assembly, calcium binding, and growth- and neurite-promoting activities.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Barthels D, Santoni MJ, Wille W, Ruppert C, Chaix JC, Hirsch MR, Fontecilla-Camps JC, Goridis C. Isolation and nucleotide sequence of mouse NCAM cDNA that codes for a Mr 79,000 polypeptide without a membrane-spanning region. EMBO J. 1987 Apr;6(4):907–914. [PubMed]
  • Becker JW, Erickson HP, Hoffman S, Cunningham BA, Edelman GM. Topology of cell adhesion molecules. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1088–1092. [PubMed]
  • Bourdon MA, Krusius T, Campbell S, Schwartz NB, Ruoslahti E. Identification and synthesis of a recognition signal for the attachment of glycosaminoglycans to proteins. Proc Natl Acad Sci U S A. 1987 May;84(10):3194–3198. [PubMed]
  • Butkowski RJ, Langeveld JP, Wieslander J, Hamilton J, Hudson BG. Localization of the Goodpasture epitope to a novel chain of basement membrane collagen. J Biol Chem. 1987 Jun 5;262(16):7874–7877. [PubMed]
  • Cardin AD, Weintraub HJ. Molecular modeling of protein-glycosaminoglycan interactions. Arteriosclerosis. 1989 Jan-Feb;9(1):21–32. [PubMed]
  • Cavener DR, Ray SC. Eukaryotic start and stop translation sites. Nucleic Acids Res. 1991 Jun 25;19(12):3185–3192. [PMC free article] [PubMed]
  • Cheung WF, Straight DL, Smith KJ, Lin SW, Roberts HR, Stafford DW. The role of the epidermal growth factor-1 and hydrophobic stack domains of human factor IX in binding to endothelial cells. J Biol Chem. 1991 May 15;266(14):8797–8800. [PubMed]
  • Corpet F. Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 1988 Nov 25;16(22):10881–10890. [PMC free article] [PubMed]
  • Couchman JR, Ljubimov AV. Mammalian tissue distribution of a large heparan sulfate proteoglycan detected by monoclonal antibodies. Matrix. 1989 Aug;9(4):311–321. [PubMed]
  • Cunningham BA, Hemperly JJ, Murray BA, Prediger EA, Brackenbury R, Edelman GM. Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing. Science. 1987 May 15;236(4803):799–806. [PubMed]
  • David G, Lories V, Decock B, Marynen P, Cassiman JJ, Van den Berghe H. Molecular cloning of a phosphatidylinositol-anchored membrane heparan sulfate proteoglycan from human lung fibroblasts. J Cell Biol. 1990 Dec;111(6 Pt 2):3165–3176. [PMC free article] [PubMed]
  • Devereux J, Haeberli P, Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. [PMC free article] [PubMed]
  • DiScipio RG, Gehring MR, Podack ER, Kan CC, Hugli TE, Fey GH. Nucleotide sequence of cDNA and derived amino acid sequence of human complement component C9. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7298–7302. [PubMed]
  • Dodge GR, Kovalszky I, Chu ML, Hassell JR, McBride OW, Yi HF, Iozzo RV. Heparan sulfate proteoglycan of human colon: partial molecular cloning, cellular expression, and mapping of the gene (HSPG2) to the short arm of human chromosome 1. Genomics. 1991 Jul;10(3):673–680. [PubMed]
  • Edelman GM, Crossin KL. Cell adhesion molecules: implications for a molecular histology. Annu Rev Biochem. 1991;60:155–190. [PubMed]
  • Ehrig K, Leivo I, Argraves WS, Ruoslahti E, Engvall E. Merosin, a tissue-specific basement membrane protein, is a laminin-like protein. Proc Natl Acad Sci U S A. 1990 May;87(9):3264–3268. [PubMed]
  • Furley AJ, Morton SB, Manalo D, Karagogeos D, Dodd J, Jessell TM. The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity. Cell. 1990 Apr 6;61(1):157–170. [PubMed]
  • Gershagen S, Fernlund P, Lundwall A. A cDNA coding for human sex hormone binding globulin. Homology to vitamin K-dependent protein S. FEBS Lett. 1987 Aug 10;220(1):129–135. [PubMed]
  • Graf J, Iwamoto Y, Sasaki M, Martin GR, Kleinman HK, Robey FA, Yamada Y. Identification of an amino acid sequence in laminin mediating cell attachment, chemotaxis, and receptor binding. Cell. 1987 Mar 27;48(6):989–996. [PubMed]
  • Gray A, Dull TJ, Ullrich A. Nucleotide sequence of epidermal growth factor cDNA predicts a 128,000-molecular weight protein precursor. Nature. 1983 Jun 23;303(5919):722–725. [PubMed]
  • Handford PA, Baron M, Mayhew M, Willis A, Beesley T, Brownlee GG, Campbell ID. The first EGF-like domain from human factor IX contains a high-affinity calcium binding site. EMBO J. 1990 Feb;9(2):475–480. [PubMed]
  • Hassell JR, Robey PG, Barrach HJ, Wilczek J, Rennard SI, Martin GR. Isolation of a heparan sulfate-containing proteoglycan from basement membrane. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4494–4498. [PubMed]
  • Heremans A, van der Schueren B, de Cock B, Paulsson M, Cassiman JJ, van den Berghe H, David G. Matrix-associated heparan sulfate proteoglycan: core protein-specific monoclonal antibodies decorate the pericellular matrix of connective tissue cells and the stromal side of basement membranes. J Cell Biol. 1989 Dec;109(6 Pt 1):3199–3211. [PMC free article] [PubMed]
  • Hostikka SL, Eddy RL, Byers MG, Höyhtyä M, Shows TB, Tryggvason K. Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1606–1610. [PubMed]
  • Hunter DD, Porter BE, Bulock JW, Adams SP, Merlie JP, Sanes JR. Primary sequence of a motor neuron-selective adhesive site in the synaptic basal lamina protein S-laminin. Cell. 1989 Dec 1;59(5):905–913. [PubMed]
  • Hunter DD, Shah V, Merlie JP, Sanes JR. A laminin-like adhesive protein concentrated in the synaptic cleft of the neuromuscular junction. Nature. 1989 Mar 16;338(6212):229–234. [PubMed]
  • Iozzo RV. Biosynthesis of heparan sulfate proteoglycan by human colon carcinoma cells and its localization at the cell surface. J Cell Biol. 1984 Aug;99(2):403–417. [PMC free article] [PubMed]
  • Kallunki P, Eddy RL, Byers MG, Kestilä M, Shows TB, Tryggvason K. Cloning of human heparan sulfate proteoglycan core protein, assignment of the gene (HSPG2) to 1p36.1----p35 and identification of a BamHI restriction fragment length polymorphism. Genomics. 1991 Oct;11(2):389–396. [PubMed]
  • Kanwar YS, Farquhar MG. Anionic sites in the glomerular basement membrane. In vivo and in vitro localization to the laminae rarae by cationic probes. J Cell Biol. 1979 Apr;81(1):137–153. [PMC free article] [PubMed]
  • Kato M, Koike Y, Suzuki S, Kimata K. Basement membrane proteoglycan in various tissues: characterization using monoclonal antibodies to the Engelbreth-Holm-Swarm mouse tumor low density heparan sulfate proteoglycan. J Cell Biol. 1988 Jun;106(6):2203–2210. [PMC free article] [PubMed]
  • Klein DJ, Brown DM, Oegema TR, Brenchley PE, Anderson JC, Dickinson MA, Horigan EA, Hassell JR. Glomerular basement membrane proteoglycans are derived from a large precursor. J Cell Biol. 1988 Mar;106(3):963–970. [PMC free article] [PubMed]
  • Komoriya A, Hortsch M, Meyers C, Smith M, Kanety H, Schlessinger J. Biologically active synthetic fragments of epidermal growth factor: localization of a major receptor-binding region. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1351–1355. [PubMed]
  • Ledbetter SR, Tyree B, Hassell JR, Horigan EA. Identification of the precursor protein to basement membrane heparan sulfate proteoglycans. J Biol Chem. 1985 Jul 5;260(13):8106–8113. [PubMed]
  • Ledbetter SR, Fisher LW, Hassell JR. Domain structure of the basement membrane heparan sulfate proteoglycan. Biochemistry. 1987 Feb 24;26(4):988–995. [PubMed]
  • Marynen P, Zhang J, Cassiman JJ, Van den Berghe H, David G. Partial primary structure of the 48- and 90-kilodalton core proteins of cell surface-associated heparan sulfate proteoglycans of lung fibroblasts. Prediction of an integral membrane domain and evidence for multiple distinct core proteins at the cell surface of human lung fibroblasts. J Biol Chem. 1989 Apr 25;264(12):7017–7024. [PubMed]
  • Mohan PS, Spiro RG. Characterization of heparan sulfate proteoglycan from calf lens capsule and proteoglycans synthesized by cultured lens epithelial cells. Comparison with other basement membrane proteoglycans. J Biol Chem. 1991 May 5;266(13):8567–8575. [PubMed]
  • Montell DJ, Goodman CS. Drosophila substrate adhesion molecule: sequence of laminin B1 chain reveals domains of homology with mouse. Cell. 1988 May 6;53(3):463–473. [PubMed]
  • Montell DJ, Goodman CS. Drosophila laminin: sequence of B2 subunit and expression of all three subunits during embryogenesis. J Cell Biol. 1989 Nov;109(5):2441–2453. [PMC free article] [PubMed]
  • Moos M, Tacke R, Scherer H, Teplow D, Früh K, Schachner M. Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin. Nature. 1988 Aug 25;334(6184):701–703. [PubMed]
  • Morrison KE, Germino GG, Reeders ST. Use of the polymerase chain reaction to clone and sequence a cDNA encoding the bovine alpha 3 chain of type IV collagen. J Biol Chem. 1991 Jan 5;266(1):34–39. [PubMed]
  • Nissinen M, Vuolteenaho R, Boot-Handford R, Kallunki P, Tryggvason K. Primary structure of the human laminin A chain. Limited expression in human tissues. Biochem J. 1991 Jun 1;276(Pt 2):369–379. [PubMed]
  • Noonan DM, Horigan EA, Ledbetter SR, Vogeli G, Sasaki M, Yamada Y, Hassell JR. Identification of cDNA clones encoding different domains of the basement membrane heparan sulfate proteoglycan. J Biol Chem. 1988 Nov 5;263(31):16379–16387. [PubMed]
  • Panayotou G, End P, Aumailley M, Timpl R, Engel J. Domains of laminin with growth-factor activity. Cell. 1989 Jan 13;56(1):93–101. [PubMed]
  • Parthasarathy N, Spiro RG. Effect of diabetes on the glycosaminoglycan component of the human glomerular basement membrane. Diabetes. 1982 Aug;31(8 Pt 1):738–741. [PubMed]
  • Paulsson M, Yurchenco PD, Ruben GC, Engel J, Timpl R. Structure of low density heparan sulfate proteoglycan isolated from a mouse tumor basement membrane. J Mol Biol. 1987 Sep 20;197(2):297–313. [PubMed]
  • Pearson WR, Lipman DJ. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. [PubMed]
  • Pikkarainen T, Eddy R, Fukushima Y, Byers M, Shows T, Pihlajaniemi T, Saraste M, Tryggvason K. Human laminin B1 chain. A multidomain protein with gene (LAMB1) locus in the q22 region of chromosome 7. J Biol Chem. 1987 Aug 5;262(22):10454–10462. [PubMed]
  • Pikkarainen T, Kallunki T, Tryggvason K. Human laminin B2 chain. Comparison of the complete amino acid sequence with the B1 chain reveals variability in sequence homology between different structural domains. J Biol Chem. 1988 May 15;263(14):6751–6758. [PubMed]
  • Ranscht B. Sequence of contactin, a 130-kD glycoprotein concentrated in areas of interneuronal contact, defines a new member of the immunoglobulin supergene family in the nervous system. J Cell Biol. 1988 Oct;107(4):1561–1573. [PMC free article] [PubMed]
  • Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science. 1987 Oct 23;238(4826):491–497. [PubMed]
  • Saku T, Furthmayr H. Characterization of the major heparan sulfate proteoglycan secreted by bovine aortic endothelial cells in culture. Homology to the large molecular weight molecule of basement membranes. J Biol Chem. 1989 Feb 25;264(6):3514–3523. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PubMed]
  • Sasaki M, Yamada Y. The laminin B2 chain has a multidomain structure homologous to the B1 chain. J Biol Chem. 1987 Dec 15;262(35):17111–17117. [PubMed]
  • Sasaki M, Kleinman HK, Huber H, Deutzmann R, Yamada Y. Laminin, a multidomain protein. The A chain has a unique globular domain and homology with the basement membrane proteoglycan and the laminin B chains. J Biol Chem. 1988 Nov 15;263(32):16536–16544. [PubMed]
  • Saunders S, Jalkanen M, O'Farrell S, Bernfield M. Molecular cloning of syndecan, an integral membrane proteoglycan. J Cell Biol. 1989 Apr;108(4):1547–1556. [PMC free article] [PubMed]
  • Sonnenberg A, Linders CJ, Modderman PW, Damsky CH, Aumailley M, Timpl R. Integrin recognition of different cell-binding fragments of laminin (P1, E3, E8) and evidence that alpha 6 beta 1 but not alpha 6 beta 4 functions as a major receptor for fragment E8. J Cell Biol. 1990 Jun;110(6):2145–2155. [PMC free article] [PubMed]
  • Soroka CJ, Farquhar MG. Characterization of a novel heparan sulfate proteoglycan found in the extracellular matrix of liver sinusoids and basement membranes. J Cell Biol. 1991 Jun;113(5):1231–1241. [PMC free article] [PubMed]
  • Südhof TC, Goldstein JL, Brown MS, Russell DW. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985 May 17;228(4701):815–822. [PubMed]
  • Timpl R. Structure and biological activity of basement membrane proteins. Eur J Biochem. 1989 Apr 1;180(3):487–502. [PubMed]
  • Vernier RL, Klein DJ, Sisson SP, Mahan JD, Oegema TR, Brown DM. Heparan sulfate--rich anionic sites in the human glomerular basement membrane. Decreased concentration in congenital nephrotic syndrome. N Engl J Med. 1983 Oct 27;309(17):1001–1009. [PubMed]
  • von Heijne G. A new method for predicting signal sequence cleavage sites. Nucleic Acids Res. 1986 Jun 11;14(11):4683–4690. [PMC free article] [PubMed]
  • Williams AF, Barclay AN. The immunoglobulin superfamily--domains for cell surface recognition. Annu Rev Immunol. 1988;6:381–405. [PubMed]
  • Yarden Y, Escobedo JA, Kuang WJ, Yang-Feng TL, Daniel TO, Tremble PM, Chen EY, Ando ME, Harkins RN, Francke U, et al. Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature. 1986 Sep 18;323(6085):226–232. [PubMed]
  • Zimmermann DR, Ruoslahti E. Multiple domains of the large fibroblast proteoglycan, versican. EMBO J. 1989 Oct;8(10):2975–2981. [PubMed]

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