Loescher, Christine M., Breitkreuz, Martin, Li, Yong, Nickel, Alexander, Unger, Andreas, Dietl, Alexander, Schmidt, Andreas, Mohamed, Belal A., Koetter, Sebastian, Schmitt, Joachim P., Krueger, Marcus ORCID: 0000-0003-2008-4582, Kruger, Martina, Toischer, Karl, Maack, Christoph, Leichert, Lars, I, Hamdani, Nazha and Linke, Wolfgang A. (2020). Regulation of titin-based cardiac stiffness by unfolded domain oxidation (UnDOx). Proc. Natl. Acad. Sci. U. S. A., 117 (39). S. 24545 - 24557. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

The relationship between oxidative stress and cardiac stiffness is thought to involve modifications to the giant muscle protein titin, which in turn can determine the progression of heart disease. In vitro studies have shown that S-glutathionylation and disulfide bonding of titin fragments could alter the elastic properties of titin; however, whether and where titin becomes oxidized in vivo is less certain. Here we demonstrate, using multiple models of oxidative stress in conjunction with mechanical loading, that immunoglobulin domains preferentially from the distal titin spring region become oxidized in vivo through the mechanism of unfolded domain oxidation (UnDOx). Via oxidation type-specific modification of titin, UnDOx modulates human cardiomyocyte passive force bidirectionally. UnDOx also enhances titin phosphorylation and, importantly, promotes nonconstitutive folding and aggregation of unfolded domains. We propose a mechanism whereby UnDOx enables the controlled homotypic interactions within the distal titin spring to stabilize this segment and regulate myocardial passive stiffness.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Loescher, Christine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Breitkreuz, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickel, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unger, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietl, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohamed, Belal A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koetter, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, Joachim P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDorcid.org/0000-0003-2008-4582UNSPECIFIED
Kruger, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toischer, KarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maack, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leichert, Lars, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamdani, NazhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Linke, Wolfgang A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-318047
DOI: 10.1073/pnas.2004900117
Journal or Publication Title: Proc. Natl. Acad. Sci. U. S. A.
Volume: 117
Number: 39
Page Range: S. 24545 - 24557
Date: 2020
Publisher: NATL ACAD SCIENCES
Place of Publication: WASHINGTON
ISSN: 0027-8424
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
S-GLUTATHIONYLATION; STRESS; AGGREGATION; MODULATION; ELASTICITY; PREDICTION; PROTEINS; SITESMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/31804

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