From Wikipedia, the free encyclopedia
Jump to: navigation, search
Myosin, light chain 2, regulatory, cardiac, slow
Symbols MYL2 ; CMH10; MLC2
External IDs OMIM160781 MGI97272 HomoloGene55462 GeneCards: MYL2 Gene
RNA expression pattern
PBB GE MYL2 209742 s at tn.png
More reference expression data
Species Human Mouse
Entrez 4633 17906
Ensembl ENSG00000111245 ENSMUSG00000013936
UniProt P10916 P51667
RefSeq (mRNA) NM_000432 NM_010861
RefSeq (protein) NP_000423 NP_034991
Location (UCSC) Chr 12:
111.35 – 111.36 Mb
Chr 5:
122.1 – 122.11 Mb
PubMed search [1] [2]

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (RLC) is a protein that in humans is encoded by the MYL2 gene.[1][2] This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).[3]

Structure and function[edit]

Cardiac, ventricular RLC (18.8 kDa) 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 MHC head,[4] 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,[5] however the dissociation rate is too slow to modulate cardiac contractility on a beat-by-beat basis.[6] Perturbing the calcium binding region of RLC through site-directed mutagenesis (D47A) decreased tension and stiffness in isolated, skinned skeletal muscle fibers,[7] suggesting that the conformational change induced by calcium binding to RLC is functionally important.[8]

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.[9] Studies have supported a role for myosin phosphatase targeting subunit 2 (MYPT2,PPP1R12B) in the dephosphorylation of RLC.[10] 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.[3] Both deamidation and phosphorylation contribute negative charge to the N-terminal region of RLC, undoubtedly altering its interaction with the C-terminal MHC 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.[11][12] 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.[13] 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.[14] 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[15] and load-independent measures of contractility.[13] 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.[13] 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.[13] 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.[16] Taken together, these studies clearly demonstrate that RLC phosphorylation regulates cardiac dynamics in beating hearts, and is critical for eliciting a normal sympathetic response.

Clinical significance[edit]

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 (PMID 8673105)(PMID 11748309). Three mutations-R58Q, D166V and IVS5-2-are associated with more malignant outcomes, manifesting with sudden cardiac death or at earlier ages (PMID 12707239) (PMID 9535554) (PMID 12404107) (PMID 12818575). It is clear from functional studies that FHC mutations in RLC affect its ability to both be phosphorylated and to bind calcium/magnesium (nicely reviewed in PMID 21415409).


  1. ^ Macera M, Szabo P, Wadgaonkar R, Siddiqui M, Verma R (Jul 1992). "Localization of the gene coding for ventricular myosin regulatory light chain (MYL2) to human chromosome 12q23-q24.3". Genomics 13 (3): 829–31. doi:10.1016/0888-7543(92)90161-K. PMID 1386340. 
  2. ^ "Entrez Gene: MYL2 myosin, light chain 2, regulatory, cardiac, slow". 
  3. ^ a b Scruggs S, Solaro R (Jun 2011). "The significance of regulatory light chain phosphorylation in cardiac physiology". Archives of Biochemistry and Biophysics 510 (2): 129–34. doi:10.1016/ PMC 3114105. PMID 21345328. 
  4. ^ Rayment I, Rypniewski W, Schmidt-Bäse K, Smith R, Tomchick D, Benning M et al. (1993). "Three-dimensional structure of myosin subfragment-1: a molecular motor". Science 261 (5117): 50–8. PMID 8316857. 
  5. ^ Morimoto K, Harrington W (Sep 1974). "Evidence for structural changes in vertebrate thick filaments induced by calcium". Journal of Molecular Biology 88 (3): 693–709. PMID 4449125. 
  6. ^ Bagshaw C (1977). "On the location of the divalent metal binding sites and the light chain subunits of vertebrate myosin". Biochemistry 16 (1): 59–67. PMID 188447. 
  7. ^ Diffee G, Patel J, Reinach F, Greaser M, Moss R (Jul 1996). "Altered kinetics of contraction in skeletal muscle fibers containing a mutant myosin regulatory light chain with reduced divalent cation binding". Biophysical Journal 71 (1): 341–50. doi:10.1016/S0006-3495(96)79231-7. PMC 1233485. PMID 8804617. 
  8. ^ Szczesna D, Ghosh D, Li Q, Gomes A, Guzman G, Arana C et al. (Mar 2001). "Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation". The Journal of Biological Chemistry 276 (10): 7086–92. doi:10.1074/jbc.M009823200. PMID 11102452. 
  9. ^ Chan J, Takeda M, Briggs L, Graham M, Lu J, Horikoshi N et al. (Mar 2008). "Identification of cardiac-specific myosin light chain kinase". Circulation Research 102 (5): 571–80. doi:10.1161/CIRCRESAHA.107.161687. PMC 2504503. PMID 18202317. 
  10. ^ Mizutani H, Okamoto R, Moriki N, Konishi K, Taniguchi M, Fujita S et al. (Jan 2010). "Overexpression of myosin phosphatase reduces Ca(2+) sensitivity of contraction and impairs cardiac function". Circulation Journal : Official Journal of the Japanese Circulation Society 74 (1): 120–8. PMID 19966500. 
  11. ^ Morano I, Hofmann F, Zimmer M, Rüegg J (Sep 1985). "The influence of P-light chain phosphorylation by myosin light chain kinase on the calcium sensitivity of chemically skinned heart fibres". FEBS Letters 189 (2): 221–4. PMID 3840099. 
  12. ^ Olsson M, Patel J, Fitzsimons D, Walker J, Moss R (Dec 2004). "Basal myosin light chain phosphorylation is a determinant of Ca2+ sensitivity of force and activation dependence of the kinetics of myocardial force development". American Journal of Physiology. Heart and Circulatory Physiology 287 (6): H2712–8. doi:10.1152/ajpheart.01067.2003. PMID 15331360. 
  13. ^ a b c d Scruggs S, Hinken A, Thawornkaiwong A, Robbins J, Walker L, de Tombe P et al. (Feb 2009). "Ablation of ventricular myosin regulatory light chain phosphorylation in mice causes cardiac dysfunction in situ and affects neighboring myofilament protein phosphorylation". The Journal of Biological Chemistry 284 (8): 5097–106. doi:10.1074/jbc.M807414200. PMC 2643522. PMID 19106098. 
  14. ^ Metzger J, Greaser M, Moss R (May 1989). "Variations in cross-bridge attachment rate and tension with phosphorylation of myosin in mammalian skinned skeletal muscle fibers. Implications for twitch potentiation in intact muscle". The Journal of General Physiology 93 (5): 855–83. PMC 2216237. PMID 2661721. 
  15. ^ Sanbe A, Fewell J, Gulick J, Osinska H, Lorenz J, Hall D et al. (Jul 1999). "Abnormal cardiac structure and function in mice expressing nonphosphorylatable cardiac regulatory myosin light chain 2". The Journal of Biological Chemistry 274 (30): 21085–94. PMID 10409661. 
  16. ^ Ding P, Huang J, Battiprolu P, Hill J, Kamm K, Stull J (Dec 2010). "Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo". The Journal of Biological Chemistry 285 (52): 40819–29. doi:10.1074/jbc.M110.160499. PMC 3003383. PMID 20943660. 

Further reading[edit]

  • Dalla Libera L, Hoffmann E, Floroff M, Jackowski G (Mar 1989). "Isolation and nucleotide sequence of the cDNA encoding human ventricular myosin light chain 2". Nucleic Acids Research 17 (6): 2360. doi:10.1093/nar/17.6.2360. PMC 317608. PMID 2704627. 
  • Kovalyov L, Shishkin S, Efimochkin A, Kovalyova M, Ershova E, Egorov T et al. (Jul 1995). "The major protein expression profile and two-dimensional protein database of human heart". Electrophoresis 16 (7): 1160–9. doi:10.1002/elps.11501601192. PMID 7498159. 
  • Wadgaonkar R, Shafiq S, Rajmanickam C, Siddiqui M (1994). "Interaction of a conserved peptide domain in recombinant human ventricular myosin light chain-2 with myosin heavy chain". Cellular & Molecular Biology Research 39 (1): 13–26. PMID 8287067. 
  • Poetter K, Jiang H, Hassanzadeh S, Master S, Chang A, Dalakas M et al. (May 1996). "Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle". Nature Genetics 13 (1): 63–9. doi:10.1038/ng0596-63. PMID 8673105. 
  • Flavigny J, Richard P, Isnard R, Carrier L, Charron P, Bonne G et al. (Mar 1998). "Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy". Journal of Molecular Medicine (Berlin, Germany) 76 (3-4): 208–14. doi:10.1007/s001090050210. PMID 9535554. 
  • Szczesna D, Ghosh D, Li Q, Gomes A, Guzman G, Arana C et al. (Mar 2001). "Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation". The Journal of Biological Chemistry 276 (10): 7086–92. doi:10.1074/jbc.M009823200. PMID 11102452. 
  • Andersen P, Havndrup O, Bundgaard H, Moolman-Smook J, Larsen L, Mogensen J et al. (Dec 2001). "Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations". Journal of Medical Genetics 38 (12): E43. doi:10.1136/jmg.38.12.e43. PMC 1734772. PMID 11748309. 
  • Ueda K, Murata-Hori M, Tatsuka M, Hosoya H (Aug 2002). "Rho-kinase contributes to diphosphorylation of myosin II regulatory light chain in nonmuscle cells". Oncogene 21 (38): 5852–60. doi:10.1038/sj.onc.1205747. PMID 12185584. 
  • Kabaeva Z, Perrot A, Wolter B, Dietz R, Cardim N, Correia J et al. (Nov 2002). "Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy". European Journal of Human Genetics : EJHG 10 (11): 741–8. doi:10.1038/sj.ejhg.5200872. PMID 12404107. 
  • Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C et al. (May 2003). "Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy". Circulation 107 (17): 2227–32. doi:10.1161/01.CIR.0000066323.15244.54. PMID 12707239. 
  • Mörner S, Richard P, Kazzam E, Hellman U, Hainque B, Schwartz K et al. (Jul 2003). "Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden". Journal of Molecular and Cellular Cardiology 35 (7): 841–9. doi:10.1016/S0022-2828(03)00146-9. PMID 12818575. 
  • Witt S, Granzier H, Witt C, Labeit S (Jul 2005). "MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination". Journal of Molecular Biology 350 (4): 713–22. doi:10.1016/j.jmb.2005.05.021. PMID 15967462. 

External links[edit]