Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor

• Published in: The Journal of biological chemistry 1992-04, Vol.267 (12), p.8544-8557
• Main Authors: MURDOCH, A. D, DODGE, G. R, COHEN, I, TUAN, R. S, IOZZO, R. V
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Base Sequence; Basement Membrane - metabolism; basement membranes; Biological and medical sciences; DNA - genetics; Epidermal Growth Factor - genetics; Fundamental and applied biological sciences. Psychology; Glycoproteins; heparan sulfate; Heparan Sulfate Proteoglycans; Heparitin Sulfate - genetics; Humans; Immunoglobulins - genetics; Immunohistochemistry; Laminin - genetics; man; Molecular Sequence Data; Nucleic Acid Hybridization; Open Reading Frames; perlecan; Proteins; proteoglycans; Proteoglycans - genetics; Receptors, LDL - genetics; Repetitive Sequences, Nucleic Acid; Sequence Alignment; Sequence Homology, Nucleic Acid; Transcription, Genetic
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)42478-7

We have determined the complete nucleotide and deduced amino acid sequence of the major protein core of the human heparan sulfate proteoglycan HSPG2/perlecan of basement membranes. Eighteen overlapping cDNA clones comprise 14.35 kilobase pairs (kb) of contiguous sequence with an open reading frame of 13.2 kb. The mature protein core, without the signal peptide of 21 amino acids, has a M(r) of 466,564. This large protein is composed of multiple modules homologous to the receptor of low density lipoprotein, laminin, neural cell adhesion molecules, and epidermal growth factor. Domain I, near the amino terminus, appears unique for the proteoglycan since it shares no significant homology with any other proteins. It contains three Ser-Gly-Asp sequences that could act as attachment sites for heparan sulfate glycosaminoglycans. Domain II is highly homologous to the LDL receptor and contains four repeats with perfect conservation of all 6 consecutive cysteines. Next is domain III which shares homology to the short arm of laminin A chain and contains four cysteine-rich regions intercalated among three globular domains. Domain IV, the largest module with greater than 2000 residues, contains 21 repeats of the immunoglobulin type as found in neural cell adhesion molecule. Near the beginning of this domain, there is a stretch of 29 hydrophobic amino acids which could allow the molecule to interact with the plasma membrane. Domain V, similar to the carboxyl-terminal globular G-domain of laminin A and to the related protein merosin, contains three globular regions and four EGF-like repeats. In situ hybridization and immunoenzymatic studies show a close association of this gene product with a variety of cells involved in the assembly of basement membranes, in addition to being localized within the stromal elements of various connective tissues. Our studies show that this proteoglycan is present in all vascularized tissues and suggest that this unique molecule has evolved from the utilization of modular structures with adhesive and growth regulatory properties.