Human Cardiac Troponin I: Difference between revisions
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== 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- | 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-tropo<scene name='90/902741/N_terminal_domain/4'>Text To Be Displayed</scene>myosin 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. | ||
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 Ca2+, 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"/> | 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 Ca2+, 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"/> | ||
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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.1 The protein contains four α helices intercalated by flexible disordered regions.<ref name="Marston"/> The structure domains include the cardiac-exclusive N terminal domain (NcTnI), the structurally rigid IT arm, the inhibitory-peptide, the switch-peptide, and the C-terminal domain.<ref name="Marston"/> | 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.1 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/4'>cardiac-exclusive N terminal domain (NcTnI)</scene>, the <scene name='90/902741/It_arm/1'>structurally rigid IT arm</scene>, the <scene name='90/902741/Inhibitory_peptide/1'>inhibitory-peptide</scene>, the <scene name='90/902741/Switch_peptide/1'>switch-peptide</scene>, and the <scene name='90/902741/C_terminal_domain/1'>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 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 Ca2+ 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 Ca2+, 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"/> | 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 Ca2+ 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 Ca2+, 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"/> | ||