Basic residues within the cardiac troponin T C terminus are required for full inhibition of muscle contraction and limit activation by calcium

Johnson, Dylan; Zhu, Li; Landim-Vieira, Maicon; Pinto, José R.; Chalovich, Joseph M.

doi:10.1074/jbc.ra119.010966

Cited by 13 publications

(80 citation statements)

References 47 publications

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“…Two other HCM mutations have been identified at R92, R92W, and R92L, leading to the suggestion that R92 is a hotspot for HCM mutations. While there are no atomic-resolution structures of this region of the thin filament, structural studies have shown that troponin T plays a role in stabilizing the tropomyosin blocked state ( Tobacman et al, 2002 ; Johnson et al, 2019 ; Madan et al, 2020 ). Molecular dynamics simulations demonstrated that mutations at R92 can change the distance between troponin T and tropomyosin ( Manning et al, 2011 ), and biochemical experiments showed that R92L decreases the affinity of troponin for tropomyosin ( Gangadharan et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation

Clippinger

Cloonan

Wang

et al. 2021

Journal of General Physiology

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Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis of familial HCM, leading to activation of adaptive mechanobiological signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation

Clippinger

Cloonan

Wang

et al. 2021

Journal of General Physiology

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“…From this better starting point, research can begin again, with new investigations of the dynamics of the filament states, the structures and properties of intermediate states, and troponin structure when myosin is attached to the filament. Also, one looks forward to further data at atomic resolution and to structural discernment of several pieces still missing, each with functional relevance: a PKA-regulated N-terminal strand of TnI (61) and three regions of TnT, the N-terminus (62,63), the C-terminus (64,65), and the linker between the core domain and the overlap region (21). Nature has thrown down the gauntlet to investigators-we have a complicated system to understand.…”

Section: Overcoming Inhibition: New Questions Revealedmentioning

confidence: 99%

Troponin Revealed: Uncovering the Structure of the Thin Filament On-Off Switch in Striated Muscle

Tobacman

2021

Biophysical Journal

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“…2 f). The importance of basic residues within this domain has been previously reported for cardiac troponin T [ 31 ].…”

Section: Resultsmentioning

confidence: 90%

“…Franklin et al further showed that Δ14 TnT protein has elevated actin-activated ATPase activity in the presence and absence of Ca 2+ [ 47 ]. More recently, Johnson et al showed that basic residues within this region in cardiac troponin T are critical for the regulation of cardiac muscle contraction [ 31 ]. Although these studies examined cardiac troponin T, the high conservation of the C-terminus between troponin isoforms strongly suggests that the mechanism is also likely to be applicable to skeletal muscle troponin T. The OCPMD mutation significantly alters the number and position of basic residues within the C-terminal region (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Ovine congenital progressive muscular dystrophy (OCPMD) is a model of TNNT1 congenital myopathy

Clayton

McNamara

Goullée

et al. 2020

acta neuropathol commun

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Ovine congenital progressive muscular dystrophy (OCPMD) was first described in Merino sheep flocks in Queensland and Western Australia in the 1960s and 1970s. The most prominent feature of the disease is a distinctive gait with stiffness of the hind limbs that can be seen as early as 3 weeks after birth. The disease is progressive. Histopathological examination had revealed dystrophic changes specifically in type I (slow) myofibres, while electron microscopy had demonstrated abundant nemaline bodies. Therefore, it was never certain whether the disease was a dystrophy or a congenital myopathy with dystrophic features. In this study, we performed whole genome sequencing of OCPMD sheep and identified a single base deletion at the splice donor site (+ 1) of intron 13 in the type I myofibre-specific TNNT1 gene (KT218690 c.614 + 1delG). All affected sheep were homozygous for this variant. Examination of TNNT1 splicing by RT-PCR showed intron retention and premature termination, which disrupts the highly conserved 14 amino acid C-terminus. The variant did not reduce TNNT1 protein levels or affect its localization but impaired its ability to modulate muscle contraction in response to Ca 2+ levels. Identification of the causative variant in TNNT1 finally clarifies that the OCPMD sheep is in fact a large animal model of TNNT1 congenital myopathy. This model could now be used for testing molecular or gene therapies.

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Basic residues within the cardiac troponin T C terminus are required for full inhibition of muscle contraction and limit activation by calcium

Cited by 13 publications

References 47 publications

Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation

Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation

Troponin Revealed: Uncovering the Structure of the Thin Filament On-Off Switch in Striated Muscle

Ovine congenital progressive muscular dystrophy (OCPMD) is a model of TNNT1 congenital myopathy

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