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精氨酸到半胱氨酸突变对 II 型胶原蛋白蛋白分泌和细胞存活的影响。

Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival.

机构信息

Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.

出版信息

Int J Mol Sci. 2018 Feb 11;19(2):541. doi: 10.3390/ijms19020541.

DOI:10.3390/ijms19020541
PMID:29439465
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5855763/
Abstract

Inherited point mutations in collagen II in humans affecting mainly cartilage are broadly classified as chondrodysplasias. Most mutations occur in the glycine (Gly) of the Gly-X-Y repeats leading to destabilization of the triple helix. Arginine to cysteine substitutions that occur at either the X or Y position within the Gly-X-Y cause different phenotypes like Stickler syndrome and congenital spondyloepiphyseal dysplasia (SEDC). We investigated the consequences of arginine to cysteine substitutions (X or Y position within the Gly-X-Y) towards the N and C terminus of the triple helix. Protein expression and its secretion trafficking were analyzed. Substitutions R75C, R134C and R704C did not alter the thermal stability with respect to wild type; R740C and R789C proteins displayed significantly reduced melting temperatures (T) affecting thermal stability. Additionally, R740C and R789C were susceptible to proteases; in cell culture, R789C protein was further cleaved by matrix metalloproteinases (MMPs) resulting in expression of only a truncated fragment affecting its secretion and intracellular retention. Retention of misfolded R740C and R789C proteins triggered an ER stress response leading to apoptosis of the expressing cells. Arginine to cysteine mutations towards the C-terminus of the triple helix had a deleterious effect, whereas mutations towards the N-terminus of the triple helix (R75C and R134C) and R704C had less impact.

摘要

人类中影响软骨的 II 型胶原的遗传点突变被广泛归类为软骨发育不良。大多数突变发生在甘氨酸（Gly）的 Gly-X-Y 重复序列中，导致三螺旋体不稳定。精氨酸到半胱氨酸的取代发生在 Gly-X-Y 中的 X 或 Y 位置，导致不同的表型，如 Stickler 综合征和先天性脊椎骨骺发育不良（SEDC）。我们研究了精氨酸到半胱氨酸取代（Gly-X-Y 中的 X 或 Y 位置）对三螺旋体的 N 和 C 末端的影响。分析了蛋白质表达及其分泌运输。R75C、R134C 和 R704C 取代物与野生型相比没有改变热稳定性；R740C 和 R789C 蛋白的熔点（T）显著降低，影响热稳定性。此外，R740C 和 R789C 容易被蛋白酶水解；在细胞培养中，R789C 蛋白进一步被基质金属蛋白酶（MMPs）切割，导致仅表达一个截断片段，影响其分泌和细胞内保留。错误折叠的 R740C 和 R789C 蛋白的保留引发内质网应激反应，导致表达细胞凋亡。三螺旋体 C 末端的精氨酸到半胱氨酸突变具有有害影响，而三螺旋体 N 末端的突变（R75C 和 R134C）和 R704C 的影响较小。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e57/5855763/dc2c2d5ff961/ijms-19-00541-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e57/5855763/85b0fdf8a216/ijms-19-00541-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e57/5855763/dc2c2d5ff961/ijms-19-00541-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e57/5855763/85b0fdf8a216/ijms-19-00541-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e57/5855763/f4c389858ddf/ijms-19-00541-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e57/5855763/40a3fa15a154/ijms-19-00541-g003.jpg
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