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Modulation of Cardiac Myofilament Activity by Protein Phosphorylation

R. John Solaro

10.1002/cphy.cp020107

Source: Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart

Originally published: 2002

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Modulation of Cardiac Myofilament Activity as A Physiological Regulatory Device
2 Major Functional Sarcomeric Proteins and the Transition from Diastole to Systole
2.1 Thin Filament Proteins in Diastole and Systole
2.2 Thick Filament Proteins in Diastole and Systole
2.3 Crossbridge and Thin Filament States in Diastole and in Systole
3 cTnI Function and Phosphorylation
3.1 Primary Structure of cTnI and Potential Sites of Phosphorylation
3.2 cTnI Protein Kinase A Sites
3.3 Functional Effects of Phosphorylation of cTnI by Protein Kinase A
3.4 cTnI Protein Kinase C Sites
3.5 Functional Effects of Phosphorylation of cTnI by Protein Kinase C
3.6 Integration of Signals for Cardiac Myocyte Hypertrophy/Failure with cTnI Protein Phosphorylation
4 cTnT Function and Phosphorylation
4.1 cTnT Primary Structure and Functional Domains
4.2 cTnT Sites of Phosphorylation
5 Tropomyosin Function and Phosphorylation
5.1 Tropomyosin isoforms and cardiac function
5.2 Tropomyosin Phosphorylation
6 MLC2 Function and Phosphorylation
6.1 Primary Structure of MLC2 and Functional Domains
6.2 Metal Binding to MLC2
6.3 MLC2 and Modulation of Striated Muscle Contraction
6.4 MLC2 Phosphorylation and Regulation of Crossbridges
7 Phosphorylation and Function of Cardiac Myosin Binding Protein C
7.1 Primary Structure of MyBP‐C and Functional Domains
7.2 Phosphorylation Sites of Cardiac MyBP‐C
8 Summary and Conclusions
Figure 1. Figure 1.

Structural units of the myofilaments in the diastolic and systolic state. Both panels show an edge of the thick filament with myosin heads (S1) extending toward the thin filament. The crossbridge is shown as comprised of the S1 portion of the myosin heavy chain with a globular head and a lever arm formed by an α‐helix that extends from the long tail making up the thick filament. Associated with the crossbridge are two light chains, MLC1 and MLC2. Associated with myosin is myosin binding protein C (MyBP‐C), which connects to titin, a structural protein. One MyBP‐C molecule is shown attached to the S2 region of myosin. Three such molecules may wrap around the thick filament. A. Diastole. In this state, Ca2+ is not bound to the regulatory site on troponin C (cTnC), cTnI is tethered to actin, and cTnT binds tightly to the actin‐Tm. This disposition of the thin‐filament proteins holds Tm and Tn in a position that physically blocks the actin‐myosin interaction and may also allosterically affect actin reactivity with myosin. B. Systole in which crossbridges are generating force. Ca2+‐binding to cTnC has triggered a reversal of the inhibited state of the thin filament and caused Tn and Tm to move on thin filament. Note that the bound crossbridge has moved Tm further on the thin filament than could have occurred with Ca2+ binding alone. The result is that the near‐neighbor crossbridge is shown reacting with actin in a force‐generating complex without Ca2+ bound to TnC. See text for further details.
Figure 2. Figure 2.

Actin domains and the three states of the myofilaments. Three actins are shown with an illustration of positions of Tm in the various states of the myofilaments. Striped domains and amino acid numbers indicate myosin binding regions. Numbers 1–4 indicate subdomains of actin, which themselves may move upon transition from the blocked to the open state.
Figure 3. Figure 3.

Schematic illustration of a myofilaments in the blocked, closed, and open states. These states are determined by the position of Tm and Tn on the thin filament, which, in the absence of Ca2+‐binding to cTnC, holds the crossbridges either in weakly attached (closed) state or physically hindered (blocked state) from reacting with actin in a force‐generating complex. Transition to the open, force‐generating state is promoted by Ca2+ binding to cTnC and interaction of the crossbridge with the thin filament.
Figure 4. Figure 4.

Schematic representation of a functional unit of the thin filament illustrating regional locations of sites of protein phosphorylation. During diastole, Ca2+ or Mg2+ is bound exclusively to the high‐affinity binding sites located in the C‐terminus of TnC. The near N‐terminus of cTnI is bound to the C‐termini of cTnT and cTnC. The inhibitory region of TnI (cross‐hatched region in the middle of TnI), is bound to actin‐tropomyosin as is a second actin binding site (residues 156–168 in the C‐terminus of cTnI). These interactions inhibit the actin–myosin force‐generating reaction. During systole, Ca2+ is bound to a single site in the N‐terminal domain of cTnC. This induces a conformational change in cTnC, which is transmitted through the thin filament proteins. There is a weakening in the interaction between TnI and actin‐Tm and a strengthening in the interaction between cTnI and cTnC as well as between cTnC and cTnT. This occurs in part because of a switch in binding of the cTnI inhibitory region from actin‐Tm to the C‐terminal half of TnC. These changes in thin filament conformation release the thin filament from its inhibited state and promote the force‐generating actin‐myosin reaction.


Figure 1.

Structural units of the myofilaments in the diastolic and systolic state. Both panels show an edge of the thick filament with myosin heads (S1) extending toward the thin filament. The crossbridge is shown as comprised of the S1 portion of the myosin heavy chain with a globular head and a lever arm formed by an α‐helix that extends from the long tail making up the thick filament. Associated with the crossbridge are two light chains, MLC1 and MLC2. Associated with myosin is myosin binding protein C (MyBP‐C), which connects to titin, a structural protein. One MyBP‐C molecule is shown attached to the S2 region of myosin. Three such molecules may wrap around the thick filament. A. Diastole. In this state, Ca2+ is not bound to the regulatory site on troponin C (cTnC), cTnI is tethered to actin, and cTnT binds tightly to the actin‐Tm. This disposition of the thin‐filament proteins holds Tm and Tn in a position that physically blocks the actin‐myosin interaction and may also allosterically affect actin reactivity with myosin. B. Systole in which crossbridges are generating force. Ca2+‐binding to cTnC has triggered a reversal of the inhibited state of the thin filament and caused Tn and Tm to move on thin filament. Note that the bound crossbridge has moved Tm further on the thin filament than could have occurred with Ca2+ binding alone. The result is that the near‐neighbor crossbridge is shown reacting with actin in a force‐generating complex without Ca2+ bound to TnC. See text for further details.



Figure 2.

Actin domains and the three states of the myofilaments. Three actins are shown with an illustration of positions of Tm in the various states of the myofilaments. Striped domains and amino acid numbers indicate myosin binding regions. Numbers 1–4 indicate subdomains of actin, which themselves may move upon transition from the blocked to the open state.



Figure 3.

Schematic illustration of a myofilaments in the blocked, closed, and open states. These states are determined by the position of Tm and Tn on the thin filament, which, in the absence of Ca2+‐binding to cTnC, holds the crossbridges either in weakly attached (closed) state or physically hindered (blocked state) from reacting with actin in a force‐generating complex. Transition to the open, force‐generating state is promoted by Ca2+ binding to cTnC and interaction of the crossbridge with the thin filament.



Figure 4.

Schematic representation of a functional unit of the thin filament illustrating regional locations of sites of protein phosphorylation. During diastole, Ca2+ or Mg2+ is bound exclusively to the high‐affinity binding sites located in the C‐terminus of TnC. The near N‐terminus of cTnI is bound to the C‐termini of cTnT and cTnC. The inhibitory region of TnI (cross‐hatched region in the middle of TnI), is bound to actin‐tropomyosin as is a second actin binding site (residues 156–168 in the C‐terminus of cTnI). These interactions inhibit the actin–myosin force‐generating reaction. During systole, Ca2+ is bound to a single site in the N‐terminal domain of cTnC. This induces a conformational change in cTnC, which is transmitted through the thin filament proteins. There is a weakening in the interaction between TnI and actin‐Tm and a strengthening in the interaction between cTnI and cTnC as well as between cTnC and cTnT. This occurs in part because of a switch in binding of the cTnI inhibitory region from actin‐Tm to the C‐terminal half of TnC. These changes in thin filament conformation release the thin filament from its inhibited state and promote the force‐generating actin‐myosin reaction.

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Article Title: Modulation of Cardiac Myofilament Activity by Protein Phosphorylation
 

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R. John Solaro. Modulation of Cardiac Myofilament Activity by Protein Phosphorylation. Compr Physiol 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 264-300. First published in print 2002. doi: 10.1002/cphy.cp020107