4633
17906
ENSG00000111245
ENSMUSG00000013936
P10916
P51667
NM_000432
NM_010861
NP_000423
NP_001371259NP_001371260
Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene.[5][6] This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).[7]
Ventricular myosin light chain-2 (MLC-2v) refers to the ventricular cardiac muscle form of myosin light chain 2 (Myl2). MLC-2v is a 19-KDa protein composed of 166 amino acids, that belongs to the EF-hand Ca2+ binding superfamily.[8] MLC-2v interacts with the neck/tail region of the muscle thick filament protein myosin to regulate myosin motility and function.[9]
Cardiac, ventricular RLC is an 18.8 kDa protein composed of 166 amino acids.[10][11] RLC and the second ventricular light chain, essential light chain (ELC, MYL3), are non-covalently bound to IQXXXRGXXXR motifs in the 9 nm S1-S2 lever arm of the myosin head,[12] both alpha (MYH6) and beta (MYH7) isoforms. Both light chains are members of the EF-hand superfamily of proteins, which possess two helix-loop-helix motifs in two globular domains connected by an alpha-helical linker.
The N-terminal EF-hand domain of RLC binds calcium/magnesium at activating concentrations,[13] however the dissociation rate is too slow to modulate cardiac contractility on a beat-by-beat basis.[14] Perturbing the calcium binding region of RLC through site-directed mutagenesis (D47A) decreased tension and stiffness in isolated, skinned skeletal muscle fibers,[15] suggesting that the conformational change induced by calcium binding to RLC is functionally important.[16]
Another mode of RLC modulation lies in its ability to be modified by phosphorylation and deamidation in the N-terminal region, resulting in significant charge alterations of the protein. RLC is phosphorylated by a cardiac-specific myosin light chain kinase (MYLK3), which was recently cloned.[17] Studies have supported a role for myosin phosphatase targeting subunit 2 (MYPT2, PPP1R12B) in the dephosphorylation of RLC.[18] Human RLC has an Asparagine at position 14 (Threonine in mouse) and a Serine at position 15 (same in mouse). Endogenous RLC exists as a mixture of unmodified (typically ~50%), singly-modified (either N14 deamidation or S15 phosphorylation) and doubly modified (N14 deamidation and S15 phosphorylation) protein.[7] Both deamidation and phosphorylation contribute negative charge to the N-terminal region of RLC, undoubtedly altering its interaction with the C-terminal myosin alpha helical domain. Functional studies have supported a role for RLC phosphorylation in modulating cardiac myosin crossbridge kinetics. It is well established that RLC phosphorylation enhances myofilament sensitivity to calcium in isometrically-contracting, skinned cardiac fibers.[19][20] It was also demonstrated that a lack of RLC phosphorylation decreases tension cost (isometric force/ATPase rate at a given pCa), suggesting that RLC phosphorylation augments cycling kinetics of myosin.[21] It has been proposed that RLC phosphorylation promotes a "swing-out" of myosin heads, facilitating weak-to-strong crossbridge binding to actin per unit calcium.[22] Additional insights regarding RLC phosphorylation in beating hearts have come from in vivo studies. Adult mice expressing a non-phosphorylatable cardiac RLC (TG-RLC(P-)) exhibited significant decreases in load-dependent[23] and load-independent measures of contractility.[21] In TG-RLC(P-), the time for the heart to reach peak elastance during ejection was elongated, ejection capacity was decreased and the inotropic response to dobutamine was blunted.[21] It is also clear that ablation of RLC phosphorylation in vivo induces alterations in the phosphorylation of other sarcomeric proteins, namely cardiac myosin binding protein C and cardiac troponin I. Moreover, RLC phosphorylation, specifically, appears to be necessary for a normal inotropic response to dobutamine.[21] In agreement with these findings, a second in vivo model, cardiac myosin light chain kinase (MYLK3) knockout (cMLCK neo/neo), showed depressed fractional shortening, progressing to left ventricular hypertrophy by 4–5 months of age.[24] Taken together, these studies clearly demonstrate that RLC phosphorylation regulates cardiac dynamics in beating hearts, and is critical for eliciting a normal sympathetic response.
MLC-2v plays an essential role in early embryonic cardiac development and function.[25] and represents one of the earliest markers of ventricular specification.[26] During early development (E7.5-8.0), MLC-2v is expressed within the cardiac crescent. The expression pattern of MLC-2v becomes restricted to the ventricular segment of the linear heart tube at E8.0 and remains restricted within the ventricle into adulthood.[26][27]
Recent studies have highlighted a critical role for MLC2v phosphorylation in cardiac torsion, function and disease.[28] In cardiac muscle, the critical phosphorylation sites have been identified as Ser14/Ser15 in the mouse heart and Ser15 in the human heart.[29] The major kinase responsible for MLC-2v phosphorylation has been identified as cardiac myosin light chain kinase (MLCK), encoded for by Mylk3.[29][30] Loss of cardiac MLCK in mice results in loss of cardiac MLC-2v phosphorylation and cardiac abnormalities.[24][31]
Mutations in MYL2 have been associated with familial hypertrophic cardiomyopathy (FHC). Ten FHC mutations have been identified in RLC: E22K, A13T, N47K, P95A, F18L, R58Q, IVS6-1G>C, L103E, IVS5-2A>G, D166V. The first three-E22K, A13T and N47K-have been associated with an unusual mid-ventricular chamber obstruction type of hypertrophy.[32][33] Three mutations-R58Q, D166V and IVS5-2-are associated with more malignant outcomes, manifesting with sudden cardiac death or at earlier ages.[34][35][36][37] Functional studies demonstrate that FHC mutations in RLC affect its ability to both be phosphorylated and to bind calcium/magnesium.[38]
MLC-2v plays an important role in cross-bridge cycling kinetics and cardiac muscle contraction.[39] MLC-2v phosphorylation at Ser14 and Ser15 increases myosin lever arm stiffness and promotes myosin head diffusion, which altogether slow down myosin kinetics and prolong the duty cycle as a means to fine-tune myofilament Ca2+ sensitivity to force.[39]
A gradient in the levels of both MLC2v phosphorylation and its kinase, cardiac MLCK, has been shown to exist across the human heart from endocardium (low phosphorylation) to epicardium (high phosphorylation).[40] The existence of this gradient has been proposed to impact cardiac torsion due to the relative spatial orientation of endocardial versus epicardial myofibers.[40] In support of this, recent studies have shown that MLC-2v phosphorylation is critical in regulating left ventricular torsion.[31][39] Variations in myosin cycling kinetics and contractile properties as a result of differential MLC-2v phosphorylation (Ser14/15) influence both epicardial and endocardial myofiber tension development and recovery to control cardiac torsion and myofiber strain mechanics.[31][39]
A number of human studies have implicated loss of MLC-2v phosphorylation in the pathogenesis of human dilated cardiomyopathy and heart failure.[29][41][42][43][44] MLC-2v dephosphorylation has also been reported in human patients carrying a rare form of familial hypertrophic cardiomyopathy (FHC) based on specific MLC-2v and MLCK mutations.[16][40][45]
MLC-2v plays a key role in the regulation of cardiac muscle contraction, through its interactions with myosin.[28] Loss of MLC-2v in mice is associated with ultrastructural defects in sarcomere assembly and results in dilated cardiomyopathy and heart failure with reduced ejection fraction, leading to embryonic lethality at E12.5.[25] More recently, a mutation in zebrafish tell tale heart (telm225) that encodes MLC-2, demonstrated that cardiac MLC-2 is required for thick filament stabilization and contractility in the embryonic zebrafish heart.[46]
The role of Myl2 mutations in pathogenesis has been determined through the generation of a number of mouse models.[39][47][48] Transgenic mice overexpressing the human MLC-2v R58Q mutation, which is associated with FHC has been shown to lead to a reduction in MLC-2v phosphorylation in hearts.[47] These mice exhibited features of FHC, including diastolic dysfunction that progressed with age.[47] Similarly, cardiac overexpression of another FHC-associated MLC-2v mutation (D166V) results in loss of MLC-2v phosphorylation in mouse hearts.[48] In addition to these findings, MLC-2v dephosphorylation in mice results in cardiac dilatation and dysfunction associated with features reminiscent of dilated cardiomyopathy, leading to heart failure and premature death.[18][31][39] Altogether these studies highlight a role for MLC-2v phosphorylation in adult heart function. These studies also suggest that torsion defects might be an early manifestation of dilated cardiomyopathy consequent to loss of MLC-2v phosphorylation.[39] MLC-2v also plays an important role in cardiac stress associated with hypertrophy.[31][39] In a novel MLC2v Ser14Ala/Ser15Ala knockin mouse model, complete loss of MLC2v (Ser14/Ser15) phosphorylation led to a worsened and differential (eccentric as opposed to concentric) response to pressure overload-induced hypertrophy.[39] In addition, mice lacking cardiac MLCK display heart failure and experience premature death in response to both pressure overload and swimming induced hypertrophy.[31] Consistent with these findings, a cardiac-specific transgenic mouse model overexpressing cardiac MLCK attenuated the response to cardiac hypertrophy induced by pressure overload.[31] Furthermore, in a cardiac-specific transgenic mouse model overexpressing skeletal myosin light chain kinase, the response to cardiac hypertrophy induced by treadmill exercise or isoproterenol was also attenuated.[49] These studies further highlight the therapeutic potential of increasing MLC-2v phosphorylation in settings of cardiac pathological stress.
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