Troponins, intrinsic disorder, and cardiomyopathy

Na, Insung; Kong, Min Jung; Straight, Shelby; Pinto, José R.; Uversky, Vladimir N.

doi:10.1515/hsz-2015-0303

Cited by 20 publications

(21 citation statements)

References 123 publications

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“…Several troponin-I domains are intrinsically disordered 34 , 39 , 40 , thus their conformation is highly responsive to the structural influence of post-translational modifications 41 , 42 . Key signaling kinases, protein kinase C, protein kinase A, protein kinase G, and p21 activated kinase 3, phosphorylate troponin-I resulting in modulation of myofilament Ca 2+ sensitivity and contractility in response to various stimuli 10 , 43 .…”

Section: Discussionmentioning

confidence: 99%

Cardiac troponins may be irreversibly modified by glycation: novel potential mechanisms of cardiac performance modulation

Janssens

Brimble

et al. 2018

Sci Rep

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Dynamic movements of the cardiac troponin complex are an important component of the cardiac cycle. Whether cardiac troponins are subjected to irreversible advanced glycation end-product (AGE) modification is unknown. This study interrogated human and rat cardiac troponin-C, troponin-I and troponin-T to identify endogenous AGE modifications using mass spectrometry (LC-MS/MS). AGE modifications were detected on two amino acid residues of human troponin-C (Lys6, Lys39), thirteen troponin-I residues (Lys36, Lys50, Lys58, Arg79, Lys117, Lys120, Lys131, Arg148, Arg162, Lys164, Lys183, Lys193, Arg204), and three troponin-T residues (Lys107, Lys125, Lys227). AGE modifications of three corresponding troponin-I residues (Lys58, Lys120, Lys194) and two corresponding troponin-T residues (Lys107, Lys227) were confirmed in cardiac tissue extracts from an experimental rodent diabetic model. Additionally, novel human troponin-I phosphorylation sites were detected (Thr119, Thr123). Accelerated AGE modification of troponin-C was evident in vitro with hexose sugar exposure. This study provides the first demonstration of the occurrence of cardiac troponin complex AGE-modifications. These irreversible AGE modifications are situated in regions of the troponin complex known to be important in myofilament relaxation, and may be of particular pathological importance in the pro-glycation environment of diabetic cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Cardiac troponins may be irreversibly modified by glycation: novel potential mechanisms of cardiac performance modulation

Janssens

Brimble

et al. 2018

Sci Rep

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“…However, in our model of slow fibres exposed to OGA inhibitors, even if fast isoforms TnT and TnI showed an increase in their O‐GlcNAcylation level, they are not expressed in slow‐twitch soleus; so, TnT O‐GlcNAcylation could not explain the modulation of the calcium activation properties of the sarcomere in this context . It is worth noting that many sarcomeric proteins, including troponins, contain intrinsically disordered regions, that might serve as crucial regulators for different cellular mechanisms . O‐GlcNAcylation preferentially occurs in secondary structures such as loop and disorganized regions instead of α‐helix or β‐strand peptides .…”

Section: O‐glcnacylation: a Modulator Of Calcium Activation Propertiementioning

confidence: 68%

O‐GlcNAcylation as a regulator of the functional and structural properties of the sarcomere in skeletal muscle: An update review

et al. 2019

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Although the O-GlcNAcylation process was discovered in 1984, its potential role in the physiology and physiopathology of skeletal muscle only emerged 20 years later. An increasing number of publications strongly support a key role of O-GlcNAcylation in the modulation of important cellular processes which are essential for skeletal muscle functions. Indeed, over a thousand of O-GlcNAcylated proteins have been identified within skeletal muscle since 2004, which belong to various classes of proteins, including sarcomeric proteins. In this review, we focused on these myofibrillar proteins, including contractile and structural proteins. Because of the modification of motor and regulatory proteins, the regulatory myosin light chain (MLC2) is related to several reports that support a key role of O-GlcNAcylation in the fine modulation of calcium activation parameters of skeletal muscle fibres, depending on muscle phenotype and muscle work. In addition, another key function of O-GlcNAcylation has recently emerged in the regulation of organization and reorganization of the sarcomere.Altogether, this data support a key role of O-GlcNAcylation in the homeostasis of sarcomeric cytoskeleton, known to be disturbed in many related muscle disorders.

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“…The degree of disorder in the cTn complex was recently linked to HCM and DCM-causing mutations. Mutations mostly cause decrease in the disorder of cTnI and cTnT instead of an increase (Na et al, 2016 ). The structure and dynamics of the N-terminal region of cTnI were also explored, revealing the multiplicity of structural profiles assumed upon binding to the cNTnC (Hwang et al, 2014 ).…”

Section: Allosteric Communication Defines the Hierarchy Of Functionalmentioning

confidence: 99%

Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype

Marques

Oliveira

2016

Front. Physiol.

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Inherited myopathies affect both skeletal and cardiac muscle and are commonly associated with genetic dysfunctions, leading to the production of anomalous proteins. In cardiomyopathies, mutations frequently occur in sarcomeric genes, but the cause-effect scenario between genetic alterations and pathological processes remains elusive. Hypertrophic cardiomyopathy (HCM) was the first cardiac disease associated with a genetic background. Since the discovery of the first mutation in the β-myosin heavy chain, more than 1400 new mutations in 11 sarcomeric genes have been reported, awarding HCM the title of the “disease of the sarcomere.” The most common macroscopic phenotypes are left ventricle and interventricular septal thickening, but because the clinical profile of this disease is quite heterogeneous, these phenotypes are not suitable for an accurate diagnosis. The development of genomic approaches for clinical investigation allows for diagnostic progress and understanding at the molecular level. Meanwhile, the lack of accurate in vivo models to better comprehend the cellular events triggered by this pathology has become a challenge. Notwithstanding, the imbalance of Ca2+ concentrations, altered signaling pathways, induction of apoptotic factors, and heart remodeling leading to abnormal anatomy have already been reported. Of note, a misbalance of signaling biomolecules, such as kinases and tumor suppressors (e.g., Akt and p53), seems to participate in apoptotic and fibrotic events. In HCM, structural and cellular information about defective sarcomeric proteins and their altered interactome is emerging but still represents a bottleneck for developing new concepts in basic research and for future therapeutic interventions. This review focuses on the structural and cellular alterations triggered by HCM-causing mutations in troponin and tropomyosin proteins and how structural biology can aid in the discovery of new platforms for therapeutics. We highlight the importance of a better understanding of allosteric communications within these thin-filament proteins to decipher the HCM pathological state.

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Troponins, intrinsic disorder, and cardiomyopathy

Cited by 20 publications

References 123 publications

Cardiac troponins may be irreversibly modified by glycation: novel potential mechanisms of cardiac performance modulation

Cardiac troponins may be irreversibly modified by glycation: novel potential mechanisms of cardiac performance modulation

O‐GlcNAcylation as a regulator of the functional and structural properties of the sarcomere in skeletal muscle: An update review

Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype

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