Fine mapping titin's C-zone: Matching cardiac myosin-binding protein C stripes with titin's super-repeats. (August 2019)

• Record Type: Journal Article
• Authors: Tonino, Paola; Kiss, Balazs; Gohlke, Jochen; Smith, John E.; Granzier, Henk
• Is Part Of: Journal of molecular and cellular cardiology. Volume 133(2019)
• Page Start: 47
• Page End: 56
• Publication Date: 2019-08
• Subjects: Myofilament structure -- Myosin -- Contractile function -- Dilated cardiomyopathy -- Hypertrophic cardiomyopathy; Ig immunoglobulin -- Fn3 fibronectin type-III -- cMyBP-C cardiac myosin-binding protein C -- DCM dilated cardiomyopathy -- HCM hypertrophic cardiomyopathy -- TTN titin gene -- C-zone region of sarcomere where titin's 11 super-repeats are located -- LMM light meromyosin -- IEM immuno-electron microscopy -- SR-SIM Super-resolution structured illumination microscopy; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.05.026
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Titin is largely comprised of serially-linked immunoglobulin (Ig) and fibronectin type-III (Fn3) domains. Many of these domains are arranged in an 11 domain super-repeat pattern that is repeated 11 times, forming the so-named titin C-zone in the A-band region of the sarcomere. Each super-repeat is thought to provide binding sites for thick filament proteins, such as cMyBP-C (cardiac myosin-binding protein C). However, it remains to be established which of titin's 11 C-zone super-repeats anchor cMyBP-C as titin contains 11 super-repeats and cMyBP-C is found in 9 stripes only. To study the layout of titin's C-zone in relation to MyBP-C, immunolabeling studies were performed on mouse skinned myocardium with antibodies to titin and cMyBP-C, using both immuno-electron microscopy and super-resolution optical microscopy. Results indicate that cMyBP-C locates near the interface between titin's C-zone super-repeats. Studies on a mouse model in which two of titin's C-zone repeats have been genetically deleted support that the first Ig domain of a super-repeat is important for anchoring cMyBP-C but also Fn3 domains located at the end of the preceding repeat. Furthermore, not all super-repeat interfaces are equal as the interface between super-repeat 1 and 2 (close to titin's D-zone) does not contain cMyBP-C. Finally, titin's C-zone does not extend all the way to the bare zone but instead terminates at the level of the second myosin crown. This study enhances insights in the molecular layout of the C-zone of titin, its relation to cMyBP-C, and its possible roles in cardiomyopathies. Graphical abstract: Unlabelled Image Highlights: The layout of titin's C-zone in relation to MyBP-C is relevant to cardiomyopathies but is unknown. Immuno-localization studies showed that cMyBP-C locates near the interface between titin super-repeats. Interface titin domains that belong to two super-repeats are likely involved in anchoring cMyBP-C. Not all super-repeat interfaces are equal: the interface between super-repeat 1 and 2 does not localize cMyBP-C. This study enhances insights in the molecular layout of titin's C-zone and its relation to cMyBP-C.