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Int. J. Mol. Sci. 2018, 19(2), 541;

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

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
Cologne Center for Musculoskeletal Biomechanics (CCMB), 50931 Cologne, Germany
Institute of Biochemistry, University of Cologne, 50931 Cologne, Germany
Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim, 60528 Frankfurt/Main, Germany
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 31 December 2017 / Revised: 4 February 2018 / Accepted: 6 February 2018 / Published: 11 February 2018
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)
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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 (Tm) 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. View Full-Text
Keywords: collagen II; chondrodysplasia; mutation; unfolded protein response; triple helix collagen II; chondrodysplasia; mutation; unfolded protein response; triple helix

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Chakkalakal, S.A.; Heilig, J.; Baumann, U.; Paulsson, M.; Zaucke, F. Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival. Int. J. Mol. Sci. 2018, 19, 541.

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