Universität zu Köln

Cimiotti, Diana, Fujita-Becker, Setsuko, Moehner, Desiree, Smolina, Natalia, Budde, Heidi, Wies, Aline, Morgenstern, Lisa, Gudkova, Alexandra, Sejersen, Thomas, Sjoeberg, Gunnar, Muegge, Andreas, Nowaczyk, Marc M., Reusch, Peter, Pfitzer, Gabriele, Stehle, Robert, Schroder, Rasmus R., Mannherz, Hans G., Kostareva, Anna and Jaquet, Kornelia (2020). Infantile restrictive cardiomyopathy: cTnI-R170G/W impair the interplay of sarcomeric proteins and the integrity of thin filaments. PLoS One, 15 (3). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

TNNI3 encoding cTnI, the inhibitory subunit of the troponin complex, is the main target for mutations leading to restrictive cardiomyopathy (RCM). Here we investigate two cTnI-R170G/W amino acid replacements, identified in infantile RCM patients, which are located in the regulatory C-terminus of cTnI. The C-terminus is thought to modulate the function of the inhibitory region of cTnI. Both cTnI-R170G/W strongly enhanced the Ca2+-sensitivity of skinned fibres, as is typical for RCM-mutations. Both mutants strongly enhanced the affinity of troponin (cTn) to tropomyosin compared to wildtype cTn, whereas binding to actin was either strengthened (R170G) or weakened (R170W). Furthermore, the stability of reconstituted thin filaments was reduced as revealed by electron microscopy. Filaments containing R170G/W appeared wavy and showed breaks. Decoration of filaments with myosin subfragment S1 was normal in the presence of R170W, but was irregular with R170G. Surprisingly, both mutants did not affect the Ca2+-dependent activation of reconstituted cardiac thin filaments. In the presence of the N-terminal fragment of cardiac myosin binding protein C (cMyBPC-C0C2) cooperativity of thin filament activation was increased only when the filaments contained wildtype cTn. No effect was observed in the presence of cTn containing R170G/W. cMyBPC-C0C2 significantly reduced binding of wildtype troponin to actin/tropomyosin, but not of both mutant cTn. Moreover, we found a direct troponin/cMyBPC-C0C2 interaction using microscale thermophoresis and identified cTnI and cTnT, but not cTnC as binding partners for cMyBPC-C0C2. Only cTn containing cTnI-R170G showed a reduced affinity towards cMyBPC-C0C2. Our results suggest that the RCM cTnI variants R170G/W impair the communication between thin and thick filament proteins and destabilize thin filaments.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Cimiotti, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Fujita-Becker, Setsuko UNSPECIFIED UNSPECIFIED UNSPECIFIED Moehner, Desiree UNSPECIFIED UNSPECIFIED UNSPECIFIED Smolina, Natalia UNSPECIFIED UNSPECIFIED UNSPECIFIED Budde, Heidi UNSPECIFIED UNSPECIFIED UNSPECIFIED Wies, Aline UNSPECIFIED UNSPECIFIED UNSPECIFIED Morgenstern, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Gudkova, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Sejersen, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Sjoeberg, Gunnar UNSPECIFIED UNSPECIFIED UNSPECIFIED Muegge, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Nowaczyk, Marc M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reusch, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfitzer, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Stehle, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroder, Rasmus R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mannherz, Hans G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kostareva, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaquet, Kornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-340662
DOI:	10.1371/journal.pone.0229227
Journal or Publication Title:	PLoS One
Volume:	15
Number:	3
Date:	2020
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CARDIAC TROPONIN-I; HYPERTROPHIC CARDIOMYOPATHY; DIASTOLIC DYSFUNCTION; GENE-MUTATIONS; PHOSPHORYLATION; TROPOMYOSIN; EXPRESSION; MUTANT; ACTIN; IDENTIFICATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34066