Substitutions for arginine at position 780 in triple helical domain of the α1(I) chain alter folding of the type I procollagen molecule and cause osteogenesis imperfecta
| Autor: | Sergey Leikin, Peter H. Byers, Elena Makareeva, Nydea A. Espinoza, Kathleen Yang, Edward L. Mertz, Guoli Sun, Diana Chen, Teri E. Klein, Juan Carlos Vera, Lynn S. Mirigian |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Circular dichroism Protein Folding Arginine lcsh:Medicine Endoplasmic Reticulum Biochemistry 0302 clinical medicine Medicine and Health Sciences Denaturation (biochemistry) Amino Acids lcsh:Science Connective Tissue Diseases Cellular Stress Responses Multidisciplinary Secretory Pathway Chemistry Organic Compounds Circular Dichroism Osteogenesis Imperfecta Extracellular Matrix Cell Processes Physical Sciences Protein folding Basic Amino Acids Cellular Structures and Organelles Procollagen Triple helix Research Article Substitution Mutation Glycine Collagen Type I 03 medical and health sciences Rheumatology Genetics Humans Point mutation lcsh:R Organic Chemistry Chemical Compounds Collagen Diseases Biology and Life Sciences Proteins Cell Biology Procollagen peptidase 030104 developmental biology Aliphatic Amino Acids Mutation Biophysics lcsh:Q Collagens 030217 neurology & neurosurgery Cysteine |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 7, p e0200264 (2018) |
| ISSN: | 1932-6203 |
| Popis: | OI is a clinically and genetically heterogeneous disorder characterized by bone fragility. More than 90% of patients are heterozygous for mutations in type I collagen genes, COL1A1 and COL1A2, and a common mutation is substitution for an obligatory glycine in the triple helical Gly-X-Y repeats. Few non-glycine substitutions in the triple helical domain have been reported; most result in Y-position substitutions of arginine by cysteine. Here, we investigated leucine and cysteine substitutions for one Y-position arginine, p.Arg958 (Arg780 in the triple helical domain) of proα1(I) chains that cause mild OI. We compared their effects with two substitutions for glycine located in close proximity. Like substitutions for glycine, those for arginine reduced the denaturation temperature of the whole molecule and caused asymmetric posttranslational overmodification of the chains. Circular dichroism and increased susceptibility to cleavage by MMP1, MMP2 and catalytic domain of MMP1 revealed significant destabilization of the triple helix near the collagenase cleavage site. On a cellular level, we observed slower triple helix folding and intracellular collagen retention, which disturbed the Endoplasmic Reticulum function and affected matrix deposition. Molecular dynamic modeling suggested that Arg780 substitutions disrupt the triple helix structure and folding by eliminating hydrogen bonds of arginine side chains, in addition to preventing HSP47 binding. The pathogenic effects of these non-glycine substitutions in bone are probably caused mostly by procollagen misfolding and its downstream effects. |
| Databáze: | OpenAIRE |
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