Aberrant binding of mutant HSP47 affects posttranslational modification of type I collagen and leads to osteogenesis imperfecta
Autoři:
Delfien Syx aff001; Yoshihiro Ishikawa aff002; Jan Gebauer aff004; Sergei P. Boudko aff002; Brecht Guillemyn aff001; Tim Van Damme aff001; Sanne D’hondt aff001; Sofie Symoens aff001; Sheela Nampoothiri aff005; Douglas B. Gould aff003; Ulrich Baumann aff004; Hans Peter Bächinger aff002; Fransiska Malfait aff001
Působiště autorů:
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
aff001; Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America
aff002; Department of Ophthalmology, UCSF School of Medicine, San Francisco, California, United States of America
aff003; Institute of Biochemistry, University of Cologne, Cologne, Germany
aff004; Amrita Institute of Medical Sciences and Research Center, Cochin, Kerala, India
aff005; Department of Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, California, United States of America
aff006
Vyšlo v časopise:
Aberrant binding of mutant HSP47 affects posttranslational modification of type I collagen and leads to osteogenesis imperfecta. PLoS Genet 17(2): e1009339. doi:10.1371/journal.pgen.1009339
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009339
Souhrn
Heat shock protein 47 (HSP47), encoded by the SERPINH1 gene, is a molecular chaperone essential for correct folding of collagens. We report a homozygous p.(R222S) substitution in HSP47 in a child with severe osteogenesis imperfecta leading to early demise. p.R222 is a highly conserved residue located within the collagen interacting surface of HSP47. Binding assays show a significantly reduced affinity of HSP47-R222S for type I collagen. This altered interaction leads to posttranslational overmodification of type I procollagen produced by dermal fibroblasts, with increased glycosylation and/or hydroxylation of lysine and proline residues as shown by mass spectrometry. Since we also observed a normal intracellular folding and secretion rate of type I procollagen, this overmodification cannot be explained by prolonged exposure of the procollagen molecules to the modifying hydroxyl- and glycosyltransferases, as is commonly observed in other types of OI. We found significant upregulation of several molecular chaperones and enzymes involved in procollagen modification and folding on Western blot and RT-qPCR. In addition, we showed that an imbalance in binding of HSP47-R222S to unfolded type I collagen chains in a gelatin sepharose pulldown assay results in increased binding of other chaperones and modifying enzymes. The elevated expression and binding of this molecular ensemble to type I procollagen suggests a compensatory mechanism for the aberrant binding of HSP47-R222S, eventually leading to overmodification of type I procollagen chains. Together, these results illustrate the importance of HSP47 for proper posttranslational modification and provide insights into the molecular pathomechanisms of the p.(R222S) alteration in HSP47, which leads to a severe OI phenotype.
Klíčová slova:
osteogenesis imperfecta – Amino acid analysis – Binding analysis – Collagens – Fibroblasts – Gelatin – Heat shock response – Secretion
Zdroje
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