COL1A1 C-propeptide mutations cause ER mislocalization of procollagen and impair C-terminal procollagen processing

Publication date: Available online 2 May 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Aileen M. Barnes, Aarthi Ashok, Elena N. Makareeva, Marina Brusel, Wayne A. Cabral, MaryAnn Weis, Catherine Moali, Emmanuel Bettler, David R. Eyre, John P. Cassella, Sergey Leikin, David J.S. Hulmes, Efrat Kessler, Joan C. MariniAbstractMutations in the type I procollagen C-propeptide occur in ~6.5% of Osteogenesis Imperfecta (OI) patients. They are of special interest because this region of procollagen is involved in α chain selection and folding, but is processed prior to fibril assembly and is absent in mature collagen fibrils in tissue. We investigated the consequences of seven COL1A1 C-propeptide mutations for collagen biochemistry in comparison to three probands with classical glycine substitutions in the collagen helix near the C-propeptide and a normal control. Procollagens with C-propeptide defects showed the expected delayed chain incorporation, slow folding and overmodification. Immunofluorescence microscopy indicated that procollagen with C-propeptide defects was mislocalized to the ER lumen, in contrast to the ER membrane localization of normal procollagen and procollagen with helical substitutions. Notably, pericellular processing of procollagen with C-propeptide mutations was defective, with accumulation of pC-collagen and/or reduced production of mature collagen. In vitro cleavage assays with BMP-1 ± PCPE-1 confirmed impaired C-...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research