Human Cardiac Troponin I: Difference between revisions
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== Introduction == | == Introduction == | ||
<StructureSection load='4Y99' size='340' side='right' caption='Core domain of human cardiac troponin' scene=''> | <StructureSection load='4Y99' size='340' side='right' caption='Core domain of human cardiac troponin (PDB code [[4y99]])' scene=''> | ||
The contraction of skeletal and cardiac muscle (striated muscle) is enabled when calcium ions bind to troponin, which causes a conformational change and pulls the tropomyosin off the myosin-binding sites on the actin filaments. The uncovering of the binding sites allows the myosin heads to bind the actin, forming a cross-bridge. Once ATP hydrolysis occurs, the power stroke needed for a muscle contraction pulls the actin and myosin filaments closer to the M line, shortening the sarcomere. <scene name='90/902741/Troponin/1'>Troponin</scene> is a trimeric complex of three proteins (<scene name='90/902741/Troponin_i/1'>I</scene>, <scene name='90/902741/Troponin_t/1'>T</scene>, and <scene name='90/902741/Troponin_c/1'>C</scene>), each with a different function that allows troponin to perform its role relating to muscle contraction. | The contraction of skeletal and cardiac muscle (striated muscle) is enabled when calcium ions bind to troponin, which causes a conformational change and pulls the tropomyosin off the myosin-binding sites on the actin filaments. The uncovering of the binding sites allows the myosin heads to bind the actin, forming a cross-bridge. Once ATP hydrolysis occurs, the power stroke needed for a muscle contraction pulls the actin and myosin filaments closer to the M line, shortening the sarcomere. <scene name='90/902741/Troponin/1'>Troponin</scene> is a trimeric complex of three proteins (<scene name='90/902741/Troponin_i/1'>I</scene>, <scene name='90/902741/Troponin_t/1'>T</scene>, and <scene name='90/902741/Troponin_c/1'>C</scene>), each with a different function that allows troponin to perform its role relating to muscle contraction. | ||
== Function == | == Function == | ||
Each of the protein subunits has an individualized function related to troponin’s role in muscle contraction. Troponin I (TnI) binds to the actin filament, inhibiting the ATPase activity from the actin-myosin binding.<ref name="Radha">DOI:10.3390/molecules26164812</ref> Troponin T (TnT) attaches to tropomyosin, anchoring it to the actin and forming the Tn-tropomyosin complex.<ref name="Radha"/> Troponin C (TnC) binds to calcium ions, inducing the conformational changes in TnI and uncovering the myosin-binding sites blocked by the tropomyosin.<ref name="Radha"/> Through this process, cross-bridge cycling occurs so that a power stroke can activate the muscle contraction. | Each of the protein subunits has an individualized function related to troponin’s role in muscle contraction. Troponin I (TnI) binds to the actin filament, inhibiting the ATPase activity from the actin-myosin binding.<ref name="Radha">DOI:10.3390/molecules26164812</ref> Troponin T (TnT) attaches to tropomyosin, anchoring it to the actin and forming the Tn-tropomyosin complex.<ref name="Radha"/> Troponin C (TnC) binds to calcium ions, inducing the <scene name='90/902741/Calcium_bound_troponin/1'>conformational changes</scene> in TnI and uncovering the myosin-binding sites blocked by the tropomyosin.<ref name="Radha"/> Through this process, cross-bridge cycling occurs so that a power stroke can activate the muscle contraction. | ||
Coinciding with different types of muscle tissue in the body, the troponin subunits have various isoforms. TnI has three different isoforms: cardiac, slow skeletal, and fast skeletal muscle.<ref name="Marston">DOI:10.1007/s10974-019-09513-1</ref> For the most part, each isoform is found exclusively in its respective muscle tissue (with one exception). During embryonic development, the slow skeletal muscle TnI isoform is expressed in the heart; however, following birth, that isoform is replaced by cardiac TnI.<ref name="Marston"/> Within the heart, the troponin complex controls cardiac output through its involuntary regulation of muscle contraction. Specifically, the diastolic relaxation and systolic contraction in the myocardium of the heart are controlled by the cardiac troponin complex and the interaction with | Coinciding with different types of muscle tissue in the body, the troponin subunits have various isoforms. TnI has three different isoforms: cardiac, slow skeletal, and fast skeletal muscle.<ref name="Marston">DOI:10.1007/s10974-019-09513-1</ref> For the most part, each isoform is found exclusively in its respective muscle tissue (with one exception). During embryonic development, the slow skeletal muscle TnI isoform is expressed in the heart; however, following birth, that isoform is replaced by cardiac TnI.<ref name="Marston"/> Within the heart, the troponin complex controls cardiac output through its involuntary regulation of muscle contraction. Specifically, the diastolic relaxation and systolic contraction in the myocardium of the heart are controlled by the cardiac troponin complex and the interaction with Ca<sup>2+</sup>, which modulates the cardiac stroke volume.<ref name="Soetkamp">DOI:10.1080/14789450.2017.1387054</ref> When the heart increases the end-diastolic volume, the stroke volume also increases, meaning that more blood is ejected from the heart with every contraction. The increase in stroke volume is done by following the Frank-Starling law, which states that an increase in sarcomere length enhances the contractile force of the myocyte.<ref name="Soetkamp"/> | ||
== Disease == | == Disease == | ||
Cardiovascular disease (CVD) is one of the leading causes of death globally, with myocardial infarctions (MI) being one of the most life-threatening events.<ref name="Radha"/> With CVD, plaque builds up in the arteries (atherosclerosis), thinning or even completely blocking them. When the arteries of the heart become blocked entirely, a MI results, which can lead to permanent cardiac tissue damage. Once cardiac muscle tissue (myocardium) dies, the body replaces it with scar tissues that do not have the same properties or functioning as the myocardium. Early diagnosis of a MI is critical to the patient's prognosis and the ability to save as much of the myocardium as possible.<ref name="Muzyk">DOI:10.33963/kp.15585</ref> During a MI, cTnT and cTnI are released into the bloodstream, making them a biomarker for a recent or ongoing heart attack. Electrocardiography (ECG) is usually the diagnostic tool used for MI’s; however, often, the results can be inconclusive even when the patient is symptomatic, with more than 40% of MI cases showing a normal ECG when admitted to the emergency room. | Cardiovascular disease (CVD) is one of the leading causes of death globally, with myocardial infarctions (MI) being one of the most life-threatening events.<ref name="Radha"/> With CVD, plaque builds up in the arteries (atherosclerosis), thinning or even completely blocking them. When the arteries of the heart become blocked entirely, a MI results, which can lead to permanent cardiac tissue damage. Once cardiac muscle tissue (myocardium) dies, the body replaces it with scar tissues that do not have the same properties or functioning as the myocardium. Early diagnosis of a MI is critical to the patient's prognosis and the ability to save as much of the myocardium as possible.<ref name="Muzyk">DOI:10.33963/kp.15585</ref> During a MI, cTnT and cTnI are released into the bloodstream, making them a biomarker for a recent or ongoing heart attack. Electrocardiography (ECG) is usually the diagnostic tool used for MI’s; however, often, the results can be inconclusive even when the patient is symptomatic, with more than 40% of MI cases showing a normal ECG when admitted to the emergency room.<ref name="Radha"/> Over the past couple of decades, point-of-care diagnostic testing and assay development for MI’s has shifted to focus on using cardiac troponin I and T as biomarkers. | ||
Most troponin is found in the body as the trimeric complex bound to tropomyosin and actin; however, there is a small portion (<2-8%) of unbound troponin subunits that reside in the cytoplasm of cardiac muscle.<ref name="Wolfe">DOI:10.1093/bjaceaccp/mkn001</ref> Upon damage to muscle tissue, the free troponin subunits are released into the bloodstream. Typical concentrations of cardiac troponin I (cTnI) in the blood are low (≤1-2 ng/mL) but can reach as high as 500 ng/mL after the onset of a MI.<ref name="Radha"/> Injury to noncardiac tissue does not demonstrate an increase of cTnI. In contrast, some cTnT assays detect proteins in the blood following skeletal muscle damage.<ref name="Thygesen">DOI:10.1161/cir.0000000000000617</ref> | Most troponin is found in the body as the trimeric complex bound to tropomyosin and actin; however, there is a small portion (<2-8%) of unbound troponin subunits that reside in the cytoplasm of cardiac muscle.<ref name="Wolfe">DOI:10.1093/bjaceaccp/mkn001</ref> Upon damage to muscle tissue, the free troponin subunits are released into the bloodstream. Typical concentrations of cardiac troponin I (cTnI) in the blood are low (≤1-2 ng/mL) but can reach as high as 500 ng/mL after the onset of a MI.<ref name="Radha"/> Injury to noncardiac tissue does not demonstrate an increase of cTnI. In contrast, some cTnT assays detect proteins in the blood following skeletal muscle damage.<ref name="Thygesen">DOI:10.1161/cir.0000000000000617</ref> | ||
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== Structural Highlights == | == Structural Highlights == | ||
Just as the other subunits of the trimeric complex, cTnI has a unique structure specific to its function. This variation between isoforms is what has allowed the development of highly specific detection assays. The overall structure of cTnI can be identified by a 210-residue long protein with a molecular weight of 24 kDa. | Just as the other subunits of the trimeric complex, cTnI has a unique structure specific to its function. This variation between isoforms is what has allowed the development of highly specific detection assays. The overall structure of cTnI can be identified by a 210-residue long protein with a molecular weight of 24 kDa.<ref name="Radha"/> The protein contains four α helices intercalated by flexible disordered regions.<ref name="Marston"/> The structure domains include the <scene name='90/902741/N_terminal_domain/9'>cardiac-exclusive N terminal domain (NcTnI)</scene>, the <scene name='90/902741/It_arm/5'>structurally rigid IT arm</scene>, the <scene name='90/902741/Inhibitory_peptide/4'>inhibitory-peptide</scene>, the <scene name='90/902741/Switch_peptide/8'>switch-peptide</scene>, and the <scene name='90/902741/C_terminal_domain/4'>C-terminal domain</scene>.<ref name="Marston"/> | ||
The cardiac isoform of TnI can be distinguished from the skeletal isoforms (both fast and slow) by the presence of an additional thirty-one N-terminal amino acids.<ref name="Soetkamp"/> The NcTnI terminal domain contains two protein kinase A (PKA)-dependent phosphorylation sites.<ref name="Cheng">DOI:10.1016/j.abb.2016.02.004</ref> The targets of PKA-mediated phosphorylation are two adjacent Serine residues (Ser 22 and Ser 23) within the N-terminus.<ref name="Marston"/> Phosphorylation of these residues stabilizes the C-terminal | The cardiac isoform of TnI can be distinguished from the skeletal isoforms (both fast and slow) by the presence of an additional thirty-one N-terminal amino acids.<ref name="Soetkamp"/> The NcTnI terminal domain contains two protein kinase A (PKA)-dependent phosphorylation sites.<ref name="Cheng">DOI:10.1016/j.abb.2016.02.004</ref> The targets of PKA-mediated phosphorylation are two adjacent Serine residues (Ser 22 and Ser 23) within the N-terminus.<ref name="Marston"/> Phosphorylation of these residues stabilizes the C-terminal α-helix through the electrostatic interactions between the phosphorylated serine residues and the neighboring basic residues.<ref name="Cheng"/> The structurally rigid IT arm serves a more significant structural function than regulatory, anchoring the trimeric troponin complex to the thin actin filament.<ref name="Cheng"/> Another structural difference between the cardiac and skeletal isoform lies in the location of the regulatory head, with a smaller angle being formed between the IT arm and sTn isoform than the cTn isoform.<ref name="Marston"/> The inhibitory-peptide region, as the name eludes, is a crucial region in the inhibitory role of cTnI. The region strongly interacts with the actin filament in the absence of Ca<sup>2+</sup> and stabilizes the tropomyosin on the myosin-binding site, preventing muscle contraction.<ref name="Cheng"/> Adjacent to the inhibitory-peptide region, the switch-peptide region has a crucial role in inducing muscle contraction. Once cTnC binds to Ca<sup>2+</sup>, the switch-peptide region is required to stabilize the N-terminus of cTnC in the “open” conformation by binding to the hydrophobic patch within the terminus, leading to the detachment from the actin filament.<ref name="Cheng"/> The C-terminal region is also known as the mobile region and acts as a second actin-tropomyosin binding site.<ref name="Cheng"/> Of all the TnI regions, the C-terminal region is considered the most conserved among different species and isoforms.<ref name="Cheng"/> | ||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||