A disease-associated glycine substitution in BP180 (type XVII collagen) leads to a local destabilization of the major collagen triple helix
| Autor: | Sally S. Twining, Mary K. Hacker, George J. Giudice, Monica Olague-Marchan, Luis A. Diaz, John A. McGrath |
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| Rok vydání: | 2000 |
| Předmět: |
Dystonin
Recombinant Fusion Proteins Collagen helix Molecular Sequence Data Mutant Glycine Gene Expression Nerve Tissue Proteins medicine.disease_cause Autoantigens Protein structure medicine Animals Humans Trypsin Amino Acid Sequence Molecular Biology Cell Line Transformed Mutation Chemistry Wild type Non-Fibrillar Collagens Molecular biology Transmembrane protein Cytoskeletal Proteins Amino Acid Substitution Ectodomain Biochemistry Mutagenesis Site-Directed Collagen Rabbits Carrier Proteins Triple helix |
| Zdroj: | Matrix Biology. 19:223-233 |
| ISSN: | 0945-053X |
| Popis: | BP180 is a homotrimeric transmembrane protein with a carboxy-terminal ectodomain that forms an interrupted collagen triple helix. Null type mutations in the BP180 gene produce a recessive subepidermal blistering disease, non-Herlitz junctional epidermolysis bullosa. Like the null mutations, a glycine substitution (G627V) within the longest BP180 collagenous domain (COL15) is also associated with the recessive skin disease; however, unlike the null mutations, this glycine substitution appears to act in a dominant fashion to give rise to a novel form of random pitting dental enamel hypoplasia. The dominant effects of this mutation were thought to be due to alterations in the assembly and/or stability of this BP180 collagenous region. To further investigate this issue, a structural analysis was performed on recombinant forms of the wild type and G627V mutant BP180 ectodomain. Both proteins were found to form collagen-like triple helices with very similar Stokes radii and melting temperatures and exhibited very similar rates of synthesis, secretion and turn-over. Tryptic digestion analysis revealed that the mutant G627V-sec180e contains an additional highly sensitive proteolytic site that maps within the region of the mutation. Thus, the disease-associated G627V mutation in BP180 does not grossly alter protein structure, but causes a local destabilization of the triple-helix that exposes sensitive residues to the in vitro effects of trypsin and possibly affects its structure-function in vivo. |
| Databáze: | OpenAIRE |
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