TY - JOUR
T1 - Fine mapping titin's C-zone
T2 - Matching cardiac myosin-binding protein C stripes with titin's super-repeats
AU - Tonino, Paola
AU - Kiss, Balazs
AU - Gohlke, Jochen
AU - Smith, John E.
AU - Granzier, Henk
N1 - Funding Information:
We are grateful to our lab members as well as to the University of Arizona Imaging Core (Life Sciences North). We are grateful to Dr. Carol Gregorio for the I103 antibody and Dr. Samantha Harris for the C5-C7 cMyBP-C antibody. This work was supported by the National Institutes of Health (R35144998) and by Foundation Leducq (TNE-13CVD04). Dr. Granzier is the Allan and Alfie Norville Endowed Chair. P.T. and H.G.: experimental design, data collection, analysis, and writing of manuscript. B.K. J.G. J.S.III, data collection, analysis and writing of manuscript. None.
Funding Information:
We are grateful to our lab members as well as to the University of Arizona Imaging Core (Life Sciences North). We are grateful to Dr. Carol Gregorio for the I103 antibody and Dr. Samantha Harris for the C5-C7 cMyBP-C antibody. This work was supported by the National Institutes of Health ( R35144998 ) and by Foundation Leducq ( TNE-13CVD04 ). Dr. Granzier is the Allan and Alfie Norville Endowed Chair.
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
KW - Contractile function
KW - Dilated cardiomyopathy
KW - Hypertrophic cardiomyopathy
KW - Myofilament structure
KW - Myosin
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U2 - 10.1016/j.yjmcc.2019.05.026
DO - 10.1016/j.yjmcc.2019.05.026
M3 - Article
C2 - 31158359
AN - SCOPUS:85066808087
SN - 0022-2828
VL - 133
SP - 47
EP - 56
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -