Universität zu Köln

Chakkalakal, Salin A., Heilig, Juliane, Baumann, Ulrich, Paulsson, Mats and Zaucke, Frank ORCID: 0000-0002-7680-9354 (2018). Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival. Int. J. Mol. Sci., 19 (2). BASEL: MDPI. ISSN 1422-0067

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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-m) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chakkalakal, Salin A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heilig, Juliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Paulsson, Mats UNSPECIFIED UNSPECIFIED UNSPECIFIED Zaucke, Frank UNSPECIFIED orcid.org/0000-0002-7680-9354 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-197148
DOI:	10.3390/ijms19020541
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	19
Number:	2
Date:	2018
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AMINO-ACID SUBSTITUTIONS; OSTEOARTHRITIC ARTICULAR-CARTILAGE; ENDOPLASMIC-RETICULUM STRESS; TRANSGENIC MOUSE MODEL; TRIPLE-HELIX; SPONDYLOEPIPHYSEAL DYSPLASIA; OSTEOGENESIS IMPERFECTA; INTRACELLULAR RETENTION; PROLYL 4-HYDROXYLASE; EXTRACELLULAR-MATRIX Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19714