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Mutation‐Dependent Capacity of the ER Proteostasis Network to Quality Control Disease‐Causing Collagen Misfolding
Author(s) -
Bikovtseva Agata,
Doan Ngoc-Duc,
DiChiara Andrew S.,
Del Rosario Amanda,
Shoulders Matthew D.
Publication year - 2020
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.2020.34.s1.09187
Subject(s) - proteostasis , endoplasmic reticulum , protein folding , mutant , triple helix , microbiology and biotechnology , chemistry , mutation , unfolded protein response , type i collagen , wild type , protein precursor , biology , biochemistry , genetics , gene , endocrinology
Osteogenesis imperfecta (OI) is an inherited disease most commonly caused by autosomal dominant mutations in collagen type‐I. OI‐causing mutations are found in both the triple helical region and the C‐propeptide region of collagen‐I. Mutations in the triple helical region cause disruption to triple helical folding, stability, and structure. Mutations in the C‐propeptide region, the C‐terminal nucleation domain of collagen‐I, disrupt the initial assembly steps in collagen folding. Currently, the mechanism by which the cellular protein folding machinery recognizes and processes these types of misfolded variants of collagen‐I is not well‐understood. Here, we report how the endoplasmic reticulum (ER) differentially processes normal and misfolding, OI‐causing collagen‐I variants. We employed state‐of‐the‐art, quantitative mass spectrometry‐based proteomic methods to determine the full complement of proteostasis network components that differentially engage wild‐type (wt) and several OI‐causing mutants of collagen‐I. We identified >75 putative proteins that might play a role in collagen‐I proteostasis, in addition to the currently known collagen‐I interactors. Interestingly, we found that while there is no significant difference in the interactomes of wild‐type (wt) and triple‐helical mutant collagen‐I variants, mutant C‐propeptide collagen‐I is well‐recognized by a number of components of the ER proteostasis network. These results indicate that the cell can specifically recognize collagen C‐propeptide misfolding, but has limited capacity to address triple‐helix domain misfolding. Our findings contribute to an understanding of how the proteostasis network reacts to different types of collagen folding defects and maintains proper collagen folding and secretion.