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3(VI) chain interferes with protein folding
* Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany;
Biophysics Section, Blackett Laboratory and Division of Medicine, Imperial College, London SW7 2AZ, U.K.;
Department of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA;
§ Department of Medicine, Section of Medical Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA;
|| Department of Neurology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA
1Correspondence: Max-Planck-Institut für Biochemie, Am Klopferspitz 18A, D-82152 Martinsried, Germany. E-mail: TIMPL{at}biochem.mpg.de
A single G1679E mutation in the amino-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 3(VI) chain
interferes with protein folding.
Key Words: haploin sufficiency • inherited disease • protein misfolding • recombinant production
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