Mechanical dissociation of the M‐band titin/obscurin complex is directionally dependent

Caldwell, Tracy A.; Sumner, Isaiah; Wright, Nathan T.

doi:10.1016/j.febslet.2015.05.023

Cited by 4 publications

(8 citation statements)

References 38 publications

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“…Titin and obscurin are the skeletal components of heart muscle, together with previously reported troponins . Mutations in obscurin and titin have been known to be associated with cardiomyopathies .…”

Section: Resultsmentioning

confidence: 99%

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Obscurin and Clusterin Elevation in Serum of Acute Myocardial Infarction Patients

Kang

Seong

Mahmud

et al. 2020

Bulletin Korean Chem Soc

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We discovered new biomarker candidates for acute myocardial infarction (AMI) using micro LC and accurate mass spectrometry. Two serum samples were pooled and used for biomarker screening. UHPLC‐LTQ‐Orbitrap analysis was used with data‐dependent acquisition followed by Sequest search. Six biomarker candidates were selected after fold change analysis of peptides in AMI patient samples compared to healthy controls. Literature search results were reflected. The six biomarker candidates were characterized and quantified using multi reaction monitoring using synthesized peptides or trypsin digested protein standards. Levels of obscurin, alpha‐1‐acid glycoprotein 1, and clusterin were significantly increased (p < 0.001) in AMI patient samples compared to levels in healthy controls, while those of antithrombin III and fibrinogen beta were not. We confirmed the diagnostic performance of obscurin and clusterin as biomarker candidates for AMI using commercial ELISA kits. Receiver operating characteristic results showed that obscurin and clusterin showed highest sensitivity and specificity for AMI diagnosis together with troponins by both of multi‐reaction monitoring analysis and ELISA.

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Section: Resultsmentioning

confidence: 99%

“…These were identified reproducibly with a high abundance by Sequest searching for pooled serums. Obscurin and titin were found only in AMI samples and known for role of myofibril organization in cardiac muscle and its cardiac organ specificity . They were included for biomarker confirmation analysis even though they got low score points.…”

Section: Resultsmentioning

confidence: 99%

Obscurin and Clusterin Elevation in Serum of Acute Myocardial Infarction Patients

Kang

Seong

Mahmud

et al. 2020

Bulletin Korean Chem Soc

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“…By elongating the dual‐domain systems, SMD gives a more controlled setting to study how these putative inter‐domain and domain/linker interactions respond to bend and stretch. SMD also simulates a physiologically reasonable timescale of stretch, and thus gives us insight into how obscurin may respond to stretch in the cell.…”

Section: Resultsmentioning

confidence: 99%

“…All steered molecular dynamics simulations were performed using the PMEMD module of the Amber 12 MD software package, using AMBERff12SB force field and in explicit solvent . For equilibrium simulations, a constant temperature of 300 K was imposed using a Langevin thermostat with a collision frequency of 1 ps −1 .…”

Section: Methodsmentioning

confidence: 99%

Obscurin is a semi‐flexible molecule in solution

et al. 2019

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Obscurin, a giant modular cytoskeletal protein, is comprised mostly of tandem immunoglobulinlike (Ig-like) domains. This architecture allows obscurin to connect distal targets within the cell. The linkers connecting the Ig domains are usually short (3-4 residues). The physical effect arising from these short linkers is not known; such linkers may lead to a stiff elongated molecule or, conversely, may lead to a more compact and dynamic structure. In an effort to better understand how linkers affect obscurin flexibility, and to better understand the physical underpinnings of this flexibility, here we study the structure and dynamics of four representative sets of dual obscurin Ig domains using experimental and computational techniques.We find in all cases tested that tandem obscurin Ig domains interact at the poles of each domain and tend to stay relatively extended in solution. NMR, SAXS, and MD simulations reveal that while tandem domains are elongated, they also bend and flex significantly. By applying this behavior to a simplified model, it becomes apparent obscurin can link targets more than 200 nm away. However, as targets get further apart, obscurin begins acting as a spring and requires progressively more energy to further elongate.

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“…Myomesin crosslinks myosin filaments and therefore must be exposed at least to some of the shear forces developing transversally to the myosin filament axis, but the extent to which myomesin is directly exposed to mechanical force in vivo remains unknown, not least because the exact orientation with respect to the filament axis can currently be only indirectly inferred, and the geometry of force transmission is therefore unclear. It is also yet unclear in which directionality mechanical forces act on the titin-obscurin, which might be relevant based on recent molecular dynamics simulations (Caldwell et al., 2015). However, it is reasonable to speculate that the extremely stable anchoring of obscurin(-like-1) to myomesin is not only structurally important, but has evolved also as functionally relevant for nanomechanical necessity, supporting the notion that the M-band is a key strain sensor in muscle sarcomeres (Agarkova et al., 2003, Pinotsis et al., 2012, Xiao and Grater, 2014).…”

Section: Discussionmentioning

confidence: 99%

Binding of Myomesin to Obscurin-Like-1 at the Muscle M-Band Provides a Strategy for Isoform-Specific Mechanical Protection

et al. 2017

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SummaryThe sarcomeric cytoskeleton is a network of modular proteins that integrate mechanical and signaling roles. Obscurin, or its homolog obscurin-like-1, bridges the giant ruler titin and the myosin crosslinker myomesin at the M-band. Yet, the molecular mechanisms underlying the physical obscurin(-like-1):myomesin connection, important for mechanical integrity of the M-band, remained elusive. Here, using a combination of structural, cellular, and single-molecule force spectroscopy techniques, we decode the architectural and functional determinants defining the obscurin(-like-1):myomesin complex. The crystal structure reveals a trans-complementation mechanism whereby an incomplete immunoglobulin-like domain assimilates an isoform-specific myomesin interdomain sequence. Crucially, this unconventional architecture provides mechanical stability up to forces of ∼135 pN. A cellular competition assay in neonatal rat cardiomyocytes validates the complex and provides the rationale for the isoform specificity of the interaction. Altogether, our results reveal a novel binding strategy in sarcomere assembly, which might have implications on muscle nanomechanics and overall M-band organization.

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Mechanical dissociation of the M‐band titin/obscurin complex is directionally dependent

Cited by 4 publications

References 38 publications

Obscurin and Clusterin Elevation in Serum of Acute Myocardial Infarction Patients

Obscurin and Clusterin Elevation in Serum of Acute Myocardial Infarction Patients

Obscurin is a semi‐flexible molecule in solution

Binding of Myomesin to Obscurin-Like-1 at the Muscle M-Band Provides a Strategy for Isoform-Specific Mechanical Protection

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