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A Bethlem myopathy Gly to Glu mutation in the von Willebrand factor A domain N2 of the collagen α3(VI) chain interferes with protein folding
Author(s) -
Sasaki Takako,
Hohenester Erhard,
Zhang RuiZhu,
Gotta Susan,
Speer Marcy C.,
Tandan Rup,
Timpl Rupert,
Chu MonLi
Publication year - 2000
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.14.5.761
Subject(s) - mutant , von willebrand factor , mutation , chemistry , recombinant dna , protein folding , homology modeling , transfection , folding (dsp implementation) , microbiology and biotechnology , biophysics , biochemistry , biology , gene , enzyme , platelet , electrical engineering , immunology , engineering
A single G1679E mutation in the ami‐no‐terminal globular domain N2 of the «3 chain of type VI collagen was found in a large family affected with Bethlem myopathy. Recombinant production of N2 (~200 residues) in transfected mammalian cells has now been used to examine the possibility that the mutation interfered with protein folding. The wild‐type form and a G1679A mutant were produced at high levels and shown to fold into a stable globular structure. Only a small amount of secretion was observed for mutants G1679E and G1679Q, which apparently were efficiently degraded within the cells. Homology modeling onto the related von Willebrand factor A1 structure indicated that substitution of G1679 by the bulky E or Q cannot be accommodated without considerable changes in the folding pattern. This suggests protein misfolding as a molecular basis for this particular mutation in Bethlem myopathy, in agreement with radioimmunoassay data showing reduced levels of domain N2 in cultured fibroblasts from two patients.—Sasaki, T., Hohenester, E., Zhang, R.‐Z., Gotta, S., Speer, M. C., Tandan, R., Timpl, R., Chu, M.‐L. A Bethlem myopathy Gly to Glu mutation in the von Willebrand factor A domain N2 of the collagen α3(VI) chain interferes with protein folding. FASEB J. 14, 761–768 (2000)