Identification of the domains within the N2A region of titin that regulate binding to actin

Tsiros, Christopher; Punch, Emily; Schaffter, Emily; Apel, Sabrina; Gage, Matthew J.

doi:10.1016/j.bbrc.2021.12.025

Cited by 2 publications

(1 citation statement)

References 20 publications

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“…The most noteworthy of these is the assertion that N2A binds directly to the actin thin filament, modulated by calcium binding; however, even more recent studies have drawn conflicting conclusions from the experimental data. Kelly et al (2021) argue that Ig86 alone binds actin in a calcium‐dependent manner; Stronczek et al (2021) were unable to find binding sites for either calcium or F‐actin in the Ig84‐86 tandem; Tsiros et al (2022) argue that only constructs that contain Ig83 and with at least 3 Ig domains can bind F‐actin, and that the calcium‐dependent binding property is lost when Ig86 is not present. Outside of actin binding, the N2A region binds to chaperones, methyltransferases, and proteases, thought to protect the region from damage and to trigger a response in the event of mechanical stress being detected.…”

Section: Variant Impact By Sarcomere Regionmentioning

confidence: 99%

Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin

Weston,

Rees,

Gautel

et al. 2023

WIREs Mechanisms of Disease

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Titin, the so‐called “third filament” of the sarcomere, represents a difficult challenge for the determination of damaging genetic variants. A single titin molecule extends across half the length of a sarcomere in striated muscle, fulfilling a variety of vital structural and signaling roles, and has been linked to an equally varied range of myopathies, resulting in a significant burden on individuals and healthcare systems alike. While the consequences of truncating variants of titin are well‐documented, the ramifications of the missense variants prevalent in the general population are less so. We here present a compendium of titin missense variants—those that result in a single amino‐acid substitution in coding regions—reported to be pathogenic and discuss these in light of the nature of titin and the variant position within the sarcomere and their domain, the structural, pathological, and biophysical characteristics that define them, and the methods used for characterization. Finally, we discuss the current knowledge and integration of the multiple fields that have contributed to our understanding of titin‐related pathology and offer suggestions as to how these concurrent methodologies may aid the further development in our understanding of titin and hopefully extend to other, less well‐studied giant proteins.This article is categorized under: Cardiovascular Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Molecular and Cellular Physiology

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Section: Variant Impact By Sarcomere Regionmentioning

confidence: 99%

Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin

Weston,

Rees,

Gautel

et al. 2023

WIREs Mechanisms of Disease

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Residual force enhancement is reduced in permeabilized fiber bundles from mdm muscles

Mishra

Nishikawa

2022

Journal of Experimental Biology

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Residual force enhancement (RFE) is the increase in steady-state force after active stretch relative to the force during isometric contraction at the same final length. The mdm mutation in mice, characterized by a small deletion in N2A titin, has been proposed to prevent N2A titin-actin interactions so that active mdm muscles are more compliant than WT. This decrease in active muscle stiffness is associated with reduced RFE. We investigated RFE in permeabilized soleus (SOL) and extensor digitorum longus (EDL) fiber bundles from wild type and mdm mice. On each fiber bundle, we performed active and passive stretches from an average sarcomere length of 2.6 - 3.0 µm at a slow rate of 0.04 µm/s, as well as isometric contractions at the initial and final lengths. One-way ANOVA showed that SOL and EDL fiber bundles from mdm mice exhibited significantly lower RFE than WT (P<0.0001). This result is consistent with previous observations in single myofibrils and intact muscles. However, it contradicts the results from a previous study which appeared to show that compensatory mechanisms could restore titin force enhancement in single fibers from mdm psoas. We suggest that residual force enhancement measured previously in mdm single fibers was an artifact of the high variability in passive tension found in degenerating fibers, which begins after ∼24 days of age. The results are consistent with the hypothesis that RFE is reduced in mdm skeletal muscles due to impaired Ca2+ dependent titin-actin interactions resulting from the small deletion in N2A titin.

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Identification of the domains within the N2A region of titin that regulate binding to actin

Cited by 2 publications

References 20 publications

Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin

Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin

Residual force enhancement is reduced in permeabilized fiber bundles from mdm muscles

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