Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca2+ sensitivity

Memo, Massimiliano; Leung, Man Ching; Ward, Douglas G.; Remedios, Cristobal dos; Morimoto, Sachio; Zhang, Lianfeng; Ravenscroft, Gianina; McNamara, Elyshia; Nowak, Kristen J.; Marston, Steven B.; Messer, Andrew E.

doi:10.1093/cvr/cvt071

Cited by 63 publications

(114 citation statements)

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“…It does require many positive charges, with as many as eight potentially involved (if His33 is included). Notably, Lys35 has been strongly implicated in autosomal dominant dilated cardiomyopathy (K36Q by the alternate numbering scheme), decreasing the calcium sensitivity of reconstituted thin filaments by 0.3-0.6 pCa units (14,34). N relaxation rates provide a window into nanosecond to picosecond (10 −9 to 10 −12 s) timescale conformational fluctuations in a protein.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, Ser5 (11) or Ser41/43 (12,13) phosphorylation has more of an impact when Ser22/23 are unphosphorylated. Finally, some mutations that cause familial dilated cardiomyopathy have been shown to mitigate the effect of Ser22/23 phosphorylation (14). Despite the physiologic importance of Ser22/23 phosphorylation in regulating cardiac calcium sensitivity, the extent of its modulatory capacity has remained elusive.…”

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confidence: 99%

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The cardiac-specific N-terminal region of troponin I positions the regulatory domain of troponin C

Hwang

Cai

Pineda-Sanabria

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The cardiac isoform of troponin I (cTnI) has a unique 31-residue N-terminal region that binds cardiac troponin C (cTnC) to increase the calcium sensitivity of the sarcomere. The interaction can be abolished by cTnI phosphorylation at Ser22 and Ser23, an important mechanism for regulating cardiac contractility. cTnC contains two EF-hand domains (the N and C domain of cTnC, cNTnC and cCTnC) connected by a flexible linker. Calcium binding to either domain favors an "open" conformation, exposing a large hydrophobic surface that is stabilized by target binding, cTnI [148][149][150][151][152][153][154][155][156][157][158] for cNTnC and cTnI for cCTnC. We used multinuclear multidimensional solution NMR spectroscopy to study cTnI in complex with cTnC. cTnI binds to the hydrophobic face of cCTnC, stabilizing an alpha helix in cTnI and a type VIII turn in cTnI [38][39][40][41]. In contrast, cTnI[1-37] remains disordered, although cTnI [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] is electrostatically tethered to the negatively charged surface of cNTnC (opposite its hydrophobic surface). The interaction does not directly affect the calcium binding affinity of cNTnC. However, it does fix the positioning of cNTnC relative to the rest of the troponin complex, similar to what was previously observed in an X-ray structure [Takeda S, et al. (2003) Nature 424(6944):35-41]. Domain positioning impacts the effective concentration of cTnI [148][149][150][151][152][153][154][155][156][157][158] presented to cNTnC, and this is how cTnI [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] indirectly modulates the calcium affinity of cNTnC within the context of the cardiac thin filament. Phosphorylation of cTnI at Ser22/23 disrupts domain positioning, explaining how it impacts many other cardiac regulatory mechanisms, like the Frank-Starling law of the heart. heart failure | dilated cardiomyopathy | hypertrophic cardiomyopathy | post-translational modification | fuzzy complex T he balance between contraction and relaxation must be carefully regulated in the heart. Impaired relaxation can lead to diastolic heart failure, whereas systolic failure is characterized by insufficient contractility. Despite having different etiologies, both forms of heart failure are similar in terms of prevalence, symptoms, and mortality (1). Of all of the signaling pathways that regulate contractile function, the best studied is sympathetic β 1 -adrenergic stimulation (2), which leads to cardiomyocyte cAMP production and activation of protein kinase A (PKA). Downstream phosphorylation of L-type calcium channels and phospholamban increases calcium fluxes, whereas phosphorylation of sarcomeric proteins, cardiac troponin I (cTnI), cardiac myosin binding protein-C, and titin (3) regulates the calciuminduced mechanical response.In human cTnI, Ser22 and Ser23 are the residues most consistently phosphorylated (4, 5). (There are some numbering inconsistencies in the literature, and we will refer to Ser22/23 in...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

The cardiac-specific N-terminal region of troponin I positions the regulatory domain of troponin C

Hwang

Cai

Pineda-Sanabria

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Although some studies document a decrease in calcium sensitivity, this has not been consistently demonstrated. One interesting observation in a number of DCM-associated mutations in the thin filament is an insensitivity to the effect of PKA-mediated phosphorylation of Ser22/Ser23 in cTnI 130 . Phosphorylation of cTnI is an important mechanism by which the calcium sensitivity of the cardiac sarcomere is regulated.…”

Section: Dilated Cardiomyopathy-associated Mutationsmentioning

confidence: 99%

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

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105

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In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

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“…In this section of the review, we analyze new findings on structural and functional implications of alterations in TM’s structural rigidity or flexibility and discuss whether the alteration in the flexibility of TM could be an initial molecular abnormality that leads to disease phenotype. Support for this idea comes from studies indicating that alterations in structural flexibility of TM may be an initial trigger for inherited HCM and DCM that are linked to TM mutations [25, 33, 40, 43, 45, 78]. …”

Section: Introduction and Scopementioning

confidence: 99%

Maladaptive modifications in myofilament proteins and triggers in the progression to heart failure and sudden death

Yar

Monasky

Solaro

2014

Pflugers Arch - Eur J Physiol

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In this review, we address the following question: Are modifications at the level of sarcomeric proteins in acquired heart failure early inducers of altered cardiac dynamics and signaling leading to remodeling and progression to decompensation? There is no doubt that most inherited cardiomyopathies are caused by mutations in proteins of the sarcomere. We think this linkage indicates that early changes at the level of the sarcomeres in acquired cardiac disorders may be significant in triggering the progression to failure. We consider evidence that there are rate-limiting mechanisms downstream of the trigger event of Ca2+ binding to troponin C, which control cardiac dynamics. We discuss new perspectives on how modifications in these mechanisms may be of relevance to redox signaling in diastolic heart failure, to angiotensin II signaling via β-arrestin, and to remodeling related to altered structural rigidity of tropomyosin. We think that these new perspectives provide a rationale for future studies directed at a more thorough understanding of the question driving our review.

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Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca2+ sensitivity

Abstract: We conclude that DCM-causing mutations in thin filament proteins abolish the relationship between myofilament Ca(2+) sensitivity and troponin I phosphorylation by PKA. We propose that this blunts the response to β-adrenergic stimulation and could be the cause of DCM in the long term.

Cited by 63 publications

References 45 publications

The cardiac-specific N-terminal region of troponin I positions the regulatory domain of troponin C

The cardiac-specific N-terminal region of troponin I positions the regulatory domain of troponin C

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Maladaptive modifications in myofilament proteins and triggers in the progression to heart failure and sudden death

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