Cardiac troponin I inhibitory peptide: location of interaction sites on troponin C

Abbott, M.Bret; Dvoretsky, Alex; Gaponenko, Vadim; Rosevear, Paul R.

doi:10.1016/s0014-5793(00)01271-0

Cited by 25 publications

(31 citation statements)

References 31 publications

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“…The PPII helix is well suited for such conformational movement due to its restricted conformational rigidity, solvent exposure, and ability to present a hydrophobic surface as well as hydrogen bonding sites. Consistent with this hypothesis, NMR and modeling studies showed that bisphosphorylation of cTnI at Ser 23/24 resulted in extension of its position on the N′-lobe of cTnC and interaction with the basic inhibitory region of cTnI (10).…”

Section: Introductionmentioning

confidence: 61%

“…In the non-phosphorylated state, the N′-extension interacts with cTnC's inactive Ca 2+ binding site I and helix A, largely through a series of weak electrostatic and hydrophobic interactions such that the acidic-N′-region is does not strongly contact cTnC (9)(10)(11). However, an important unanswered question is the role of the conserved acidic-N′-region of cTnI in modulating cardiac function.…”

Section: Introductionmentioning

confidence: 99%

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Role of the acidic N′ region of cardiac troponin I in regulating myocardial function

et al. 2007

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Cardiac troponin I (cTnI) phosphorylation helps regulate myocardial contractility and relaxation during β-adrenergic stimulation. cTnI differs from the skeletal isoform in that it has a cardiac specific N′-extension of 32 residues (N′-extension). The role of the acidic-N′-region in modulating cardiac contractility has not been fully defined. To test the hypothesis that the acidic-N′-region of cTnI helps regulate myocardial function, we generated cardiac-specific transgenic mice in which residues 2-11 (cTnI Δ2-11 ) were deleted. The hearts displayed significantly decreased contraction and relaxation under basal and β-adrenergic stress compared to non-transgenic hearts, with a reduction in maximal Ca 2+ dependent force and maximal Ca 2+ -activated Mg 2+ -ATPase activity. However, Ca 2+ sensitivity of force development and cTnI-Ser 23/24 phosphorylation were not affected. NMR amide proton/ nitrogen chemical shift analysis shows that phosphorylation at Ser 23/24 in cTnI and cTnI Δ2-11 decrease interactions with the N-lobe of cardiac troponin C. We hypothesized that phosphorylation at Ser 23/24 induces a large conformational change positioning the conserved acidic-N-region to compete with actin for the inhibitory region of cTnI. Consistent with this hypothesis, deletion of the conserved acidic-N′-region results in a decrease in myocardial contractility in the cTnI Δ2-11 mice demonstrating the importance of acidic-N′-region in regulating myocardial contractility and mediating the heart's response to β-AR stimulation.

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Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Role of the acidic N′ region of cardiac troponin I in regulating myocardial function

et al. 2007

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“…Thr-144 is important because it is located within residues 138-149 (1,869), the inhibitory peptide (IP) region of TnI (338,652,857). The IP region of TnI is the minimum sequence needed to inhibit strong interactions between actin and myosin in the absence of Ca 2ϩ (857,896), and it toggles between actin (low [Ca 2ϩ ]) and TnC during the Ca 2ϩ transient.…”

Section: Downstream Translocation and Other Signaling Pathwaysmentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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“…Although there are many precedents of short peptides having different structures in solution and in complex with other subunits, NMR of the peptide bound to TnC also failed to detect substantial helical structure (47). This might have been caused by nonspecific binding of the inhibitory peptide to the Cterminal domain of TnC (48), but the issue remains unresolved. The four intrasubunit dipolar distances presented here are consistent with the theoretical prediction of a helix-loop-helix structure (47).…”

Section: Models Of Binary Complexmentioning

confidence: 99%

Structure of the inhibitory region of troponin by site directed spin labeling electron paramagnetic resonance

Brown

Sale

Hills

et al. 2002

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

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Site-directed spin labeling EPR (SDSL-EPRtroponin I ͉ spin labels ͉ Fourier transform electron paramagnetic resonance ͉ DEER ͉ dipolar R egulation of striated muscle contraction is associated with Ca 2ϩ -dependent structural transitions in the muscle thin filament, which is composed of the troponin complex, tropomyosin, and actin. Troponin is composed of three components: TnC, which binds Ca 2ϩ ; TnI, which inhibits actomyosin activity; and TnT, which anchors TnC and TnI to tropomyosin. Muscle contraction is initiated by the binding of Ca 2ϩ to the N-lobe regulatory sites of TnC. The N lobe then undergoes a structural transition from a closed to an open form, which then facilitates the release of the inhibitory region of TnI from actin, binding to TnC and stimulation of the actomyosin ATPase. The mechanism of this signaling pathway is still tentative (for review, see ref. 1).Crystal and NMR structures are available for TnC and several complexes of TnC with TnI fragments. The crystal structure of TnC reveals a dumbbell-shaped protein consisting of two globular domains, joined by a 22-residue central ␣-helix (2-4). Each domain contains a hydrophobic cleft and two helix-loop-helix EF-hand metal binding motifs; two high-affinity Ca 2ϩ ͞Mg 2ϩ sites in the C-terminal domain (sites III and IV) and two low-affinity Ca 2ϩ specific sites in the N-terminal domain (sites I and II). In skeletal TnC, sites III and IV are permanently occupied by Mg 2ϩ and facilitate the structural binding of TnC to the contractile apparatus (5). Binding of Ca 2ϩ to sites I and II is the physiological trigger for muscle contraction. In cardiac TnC, binding site I is inactive and Ca 2ϩ binding to site II does not induce as large a structural change as observed in skeletal TnC (6). TnI is capable of inhibiting actomyosin ATPase in the absence of other subunits, but Ca 2ϩ -dependent regulation requires TnC, TnT, and tropomyosin. The inhibitory region (skTnI 96-117) alone can fully inhibit actomyosin ATPase activity (7) possibly by binding either to actin or to TnC in the ''on'' or ''off'' states (8-10). The corresponding residues for the cardiac inhibitory region are 129-150 because of a unique Ϸ32 residue N-terminal extension of cTnI.Structural information for the intact troponin complex is limited to low-resolution neutron diffraction and electron microscopy studies (11-13), though several high-resolution structures of TnC with bound TnI peptides are available. Two computational models have been recently proposed for the binary complex of TnC and TnI (14,15). Both models have TnI and TnC in an antiparallel arrangement with multiple interaction sites between the two subunits. NMR, crystallography, and neutron scattering was used by Tung et al. (15) to develop a computational model of the binary complex in which TnI winds around TnC in either a left-handed manner (model ''L'') or a right-handed manner (model ''R''). In both structures, the inhibitory region of TnI is modeled as a flexible ␤-hairpin in close proximity to the central helix of TnC. ...

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Cardiac troponin I inhibitory peptide: location of interaction sites on troponin C

Cited by 25 publications

References 31 publications

Role of the acidic N′ region of cardiac troponin I in regulating myocardial function

Role of the acidic N′ region of cardiac troponin I in regulating myocardial function

Designing Heart Performance by Gene Transfer

Structure of the inhibitory region of troponin by site directed spin labeling electron paramagnetic resonance

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