Biology:CSRP3

From HandWiki
A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Cysteine and glycine-rich protein 3 also known as cardiac LIM protein (CLP) or muscle LIM protein (MLP) is a protein that in humans is encoded by the CSRP3 gene.[1]

CSRP3 IS a small 194 amino acid protein, which is specifically expressed in skeletal and cardiac muscle.[2][3] In rodents, CSRP3 has also been found to be expressed in neurons.[4]

Gene

The CSRP3 gene was discovered in rat in 1994.[1] In humans it was mapped to chromosome 11p15.1,[5][6] where it spans a 20kb genomic region, organized in 6 exons. The full length transcript is 0.8kb,[5][7] while a splice variant, originating from the alternative splicing of exons 3 and 4, was recently identified and designated MLP-b.[8]

Structure

MLP contains two LIM domains (LIM1 and LIM2), each being surrounded by glycine-rich regions, and the two separated by more than 50 residues.[9] LIM domains offer a remarkable ability for protein-protein interactions.[10] Furthermore, MLP carries a nuclear localization signal at amino acid positions 64-69 [11] MLP can be acetylated/deacetylated at the position 69 lysine residue (K69), by acetyltransferase (PCAF) and histone deacetylase 4 (HDAC4), respectively.[12] In myocytes, MLP has the ability to oligomerize, forming dimers, trimers and tetramers, an attribute that impacts its interactions, localization and function.[13]

Protein interactions and localization

MLP has been identified to bind to an increasing list of proteins, exhibiting variable subcellular localization and diverse functional properties. In particular, MLP interacts with proteins at the:

  1. Z-line, including telethonin (T-cap), alpha-actinin (ACTN), cofilin-2 (CFL2), calcineurin, HDAC4, MLP-b as well as to MLP itself;[7][8][12][14][15][16][17]
  2. costameres, where it binds to zyxin, integrin linked kinase (ILK) and beta1-spectrin;[14][18][19]
  3. intercalated discs, where it associates with the nebulin-related anchoring protein (NRAP);[20]
  4. nucleus, where it binds to the transcription factors MyoD, myogenin and MRF4.[21]

M-line as well as plasma membrane localization of MLP has also been observed, however, the protein associations mediating this subcellular distribution are currently unknown.[13][22] These diverse localization patterns and binding partners of MLP suggest a multitude of roles relating both to the striated myocyte cytoskeleton and the nucleus.[23] The role of MLP in each of these two cellular compartments appears to be dynamic, with studies demonstrating nucleocytoplasmic shuttling, driven by its nuclear localization signal, over time and under different conditions.[23]

Function

In the nucleus, MLP acts as a positive regulator of myogenesis and promotes myogenic differentiation.[1] Overexpression of MLP enhances myotube differentiation, an effect attributed to the direct association of MLP with muscle specific transcription factors such as MyoD, myogenin and MRF4 and consequently the transcriptional control of fundamental muscle-specific genes.[1][8][21] In the cytoplasm, MLP is an important scaffold protein, implicated in various cytoskeletal macromolecular complexes, at the sarcomeric Z-line, the costameres, and the microfilaments.[7][8][12][14][15][16][17] At the Z-line, MLP interacts with different Z-line components [7][8][12][14][15][16][17][24][25] and acts as a scaffold protein promoting the assembly of macromolecular complexes along sarcomeres and actin-based cytoskeleton [7][18][20][26][27] Moreover, since the Z-line acts as a stretch sensor,[28][29][30][31] MLP is believed to be involved in mechano-signaling processes. Indeed, cardiomyocytes from MLP transgenic or knock-out mouse exhibit defective intrinsic stretch responses, due to selective loss of passive stretch sensing.[7][22] At the costameres, another region implicated in force transmission, MLP is thought to be contributing in mechanosensing through its interactions with β1 spectrin and zyxin. However, the precise role of MLP at the costameres has not been extensively investigated yet.

At the microfilaments, MLP is implicated in actin remodeling (or actin dynamics) through its interaction with cofilin-2 (CFL2). Binding of MLP to CFL2 enhances the CFL2-dependent F-actin depolymerization,[15] with a recent study demonstrating that MLP can act directly on actin cytoskeleton dynamics through direct binding that stabilizes and crosslinks actin filaments into bundles.[32]

Additionally, MLP is indirectly related to calcium homeostasis and energy metabolism. Specifically, acetylation of MLP increases the calcium sensitivity of myofilaments and regulates contractility,[12] while the absence of MLP causes alterations in calcium signaling (intracellular calcium handling) with defects in excitation-contraction coupling.[33][34][35] Furthermore, lack of MLP leads to local loss of mitochondria and energy deficiency.[36]

Animal studies

In rodents, MLP is transiently expressed in amacrine cells of the retina during postnatal development.[37] In the adult nervous system it is expressed upon axonal injury,[38] where it plays an important role during regenerative processes, functioning as an actin cross-linker, thereby facilitating filopodia formation and increasing growth cone motility.[4]

Clinical significance

MLP is directly associated with striated muscle diseases.[39] Mutations in the CSRP3 gene have been detected in patients with dilated cardiomyopathy (DCM) [e.g. G72R and K69R], and hypertrophic cardiomyopathy (HCM) [e.g. L44P, S46R, S54R/E55G, C58G, R64C, Y66C, Q91L, K42/fs165], while the most frequent MLP mutation, W4R, has been found in both of these patient populations.[7][11][22][40][41][42][43] Biochemical and functional studies have been performed for some of these mutant proteins, and reveal aberrant localization and interaction patterns, leading to impaired molecular and cellular functions. For example, the W4R mutation abolishes the MLP/T-cap interaction, leading to mislocalization of T-cap, Z-line instability and severe sarcomeric structural defects.[7] The C58G mutation causes reduced protein stability due to enhanced ubiquitin-dependent proteasome degradation[40] while the K69L mutation, which is within the predicted nuclear localization signal of MLP, abolishes the MLP/α-actinin interaction and causes altered subcellular distribution of the mutant protein, showing predominant perinuclear localization.[43] Alterations in the protein expression levels of MLP, its oligomerization or splicing have also been described in human cardiac and skeletal muscle diseases: both MLP protein levels and oligomerization are down-regulated in human heart failure,[13][16] while MLP levels are significantly changed in different skeletal myopathies, including facioscapulohumeral muscular dystrophy, nemaline myopathy and limb girdle muscular dystrophy type 2B.[44][45][46] Moreover, significant changes in MLP-b protein expression levels, as well as deregulation of the MLP:MLP-b ratio have been detected in limb girdle muscular dystrophy type 2A, Duchenne muscular dystrophy and dermatomyositis patients.[8]

Animal models

Animal models are providing insight into MLP's function in striated muscle. Ablation of Mlp (MLP-/-) in mice affects all striated muscles, although the cardiac phenotype is more severe, leading to alterations in cardiac pressure and volume, aberrant contractility, development of dilated cardiomyopathy with hypertrophy and progressive heart failure.[27][33][47] At the histological level there is dramatic disruption of the cardiomyocyte cytoarchitecture at multiple levels, and pronounced fibrosis.[20][27][35][48] Other cellular changes included alterations in intracellular calcium handling, local loss of mitochondria and energy deficiency.[33][34][35] Crossing MLP-/- mice with phospholamban (PLN) -/-, or β2-adrenergic receptor (β2-AR) -/-, or angiotensin II type 1a receptor (AT1a) -/-, or β-adrenergic receptor kinase 1 inhibitor (bARK1) -/- mice, as well as overexpressing calcineurin rescued their cardiac function, through a series of only partly understood molecular mechanisms.[49][50][51][52][53] Conversely crossing MLP-/- mice with β1-adrenergic receptor (β1-AR) -/- mice was lethal, while crossing MLP-/- mice with calcineurin -/- mice, enhanced fibrosis and cardiomyopathy.[49][50] A gene knockin mouse model harboring the human MLP-W4R mutation developed HCM and heart failure, while ultrastructural analysis of its cardiac tissue revealed myocardial disarray and significant fibrosis, increased nuclear localization of MLP concomitantly with reduced sarcomeric Z-line distribution.[22] Alterations in MLP nucleocytoplasmic shuttling, which are possibly modulated by changes in its oligomerization status, have also been implicated in hypertrophy and heart failure, independently of mutations.[13][23] Studies in Drosophila revealed that genetic ablation of Mlp84B, the Drosophila homolog of MLP, was associated with pupal lethality and impaired muscle function.[24] Mechanical studies of Mlp84B-null flight muscles indicate that loss of Mlp84B results in decreased muscle stiffness and power generation.[54] Cardiac-specific ablation of Mlp84B caused decreased lifespan, impaired diastolic function and disturbances in cardiac rhythm.[55] Overall, these animal models have provided critical evidence on the functional significance of MLP in striated muscle physiology and pathophysiology.

Notes

References

  1. ↑ 1.0 1.1 1.2 1.3 "Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation". Cell 79 (2): 221–31. October 1994. doi:10.1016/0092-8674(94)90192-9. PMID 7954791. 
  2. ↑ "Back to square one: what do we know about the functions of muscle LIM protein in the heart?". Journal of Muscle Research and Cell Motility 29 (6–8): 155–8. 2008. doi:10.1007/s10974-008-9159-4. PMID 19115046. 
  3. ↑ "Muscle LIM protein in heart failure". Experimental and Clinical Cardiology 7 (2–3): 104–5. 2001. PMID 19649232. 
  4. ↑ 4.0 4.1 "Muscle LIM Protein Is Expressed in the Injured Adult CNS and Promotes Axon Regeneration" (in English). Cell Reports 26 (4): 1021–1032.e6. January 2019. doi:10.1016/j.celrep.2018.12.026. PMID 30673598. 
  5. ↑ 5.0 5.1 "Characterization of a human cardiac gene which encodes for a LIM domain protein and is developmentally expressed in myocardial development". Journal of Molecular and Cellular Cardiology 28 (6): 1203–10. June 1996. doi:10.1006/jmcc.1996.0111. PMID 8782062. 
  6. ↑ "Mapping of a human LIM protein (CLP) to human chromosome 11p15.1 by fluorescence in situ hybridization". Genomics 28 (3): 602–3. August 1995. doi:10.1006/geno.1995.1200. PMID 7490106. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy". Cell 111 (7): 943–55. December 2002. doi:10.1016/s0092-8674(02)01226-6. PMID 12507422. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "Muscle lim protein isoform negatively regulates striated muscle actin dynamics and differentiation". The FEBS Journal 281 (14): 3261–79. July 2014. doi:10.1111/febs.12859. PMID 24860983. 
  9. ↑ "The cysteine-rich protein family of highly related LIM domain proteins". The Journal of Biological Chemistry 270 (48): 28946–54. December 1995. doi:10.1074/jbc.270.48.28946. PMID 7499425. 
  10. ↑ "MLP (muscle LIM protein) as a stress sensor in the heart". Pflügers Archiv 462 (1): 135–42. July 2011. doi:10.1007/s00424-011-0961-2. PMID 21484537. 
  11. ↑ 11.0 11.1 "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin". Molecular Genetics and Metabolism 88 (1): 78–85. May 2006. doi:10.1016/j.ymgme.2005.10.008. PMID 16352453. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "HDAC4 and PCAF bind to cardiac sarcomeres and play a role in regulating myofilament contractile activity". The Journal of Biological Chemistry 283 (15): 10135–46. April 2008. doi:10.1074/jbc.M710277200. PMID 18250163. 
  13. ↑ 13.0 13.1 13.2 13.3 "Cardiac dysfunction and heart failure are associated with abnormalities in the subcellular distribution and amounts of oligomeric muscle LIM protein". American Journal of Physiology. Heart and Circulatory Physiology 292 (1): H259–69. January 2007. doi:10.1152/ajpheart.00766.2006. PMID 16963613. 
  14. ↑ 14.0 14.1 14.2 14.3 "Comparison of three members of the cysteine-rich protein family reveals functional conservation and divergent patterns of gene expression". The Journal of Biological Chemistry 272 (43): 27484–91. October 1997. doi:10.1074/jbc.272.43.27484. PMID 9341203. 
  15. ↑ 15.0 15.1 15.2 15.3 "Muscle LIM protein interacts with cofilin 2 and regulates F-actin dynamics in cardiac and skeletal muscle". Molecular and Cellular Biology 29 (22): 6046–58. November 2009. doi:10.1128/MCB.00654-09. PMID 19752190. 
  16. ↑ 16.0 16.1 16.2 16.3 "Decreased expression of the cardiac LIM domain protein MLP in chronic human heart failure". Circulation 101 (23): 2674–7. June 2000. doi:10.1161/01.cir.101.23.2674. PMID 10851202. 
  17. ↑ 17.0 17.1 17.2 "Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc". Proceedings of the National Academy of Sciences of the United States of America 102 (5): 1655–60. February 2005. doi:10.1073/pnas.0405488102. PMID 15665106. Bibcode: 2005PNAS..102.1655H. 
  18. ↑ 18.0 18.1 "The muscle regulatory and structural protein MLP is a cytoskeletal binding partner of betaI-spectrin". Journal of Cell Science 113 (9): 1553–64. May 2000. PMID 10751147. 
  19. ↑ "Zebrafish integrin-linked kinase is required in skeletal muscles for strengthening the integrin-ECM adhesion complex". Developmental Biology 318 (1): 92–101. June 2008. doi:10.1016/j.ydbio.2008.03.024. PMID 18436206. 
  20. ↑ 20.0 20.1 20.2 "Alterations at the intercalated disk associated with the absence of muscle LIM protein". The Journal of Cell Biology 153 (4): 763–72. May 2001. doi:10.1083/jcb.153.4.763. PMID 11352937. 
  21. ↑ 21.0 21.1 "Muscle LIM protein promotes myogenesis by enhancing the activity of MyoD". Molecular and Cellular Biology 17 (8): 4750–60. August 1997. doi:10.1128/mcb.17.8.4750. PMID 9234731. 
  22. ↑ 22.0 22.1 22.2 22.3 "A common MLP (muscle LIM protein) variant is associated with cardiomyopathy". Circulation Research 106 (4): 695–704. March 2010. doi:10.1161/CIRCRESAHA.109.206243. PMID 20044516. 
  23. ↑ 23.0 23.1 23.2 "Myocyte remodeling in response to hypertrophic stimuli requires nucleocytoplasmic shuttling of muscle LIM protein". Journal of Molecular and Cellular Cardiology 47 (4): 426–35. October 2009. doi:10.1016/j.yjmcc.2009.04.006. PMID 19376126. 
  24. ↑ 24.0 24.1 "The Drosophila muscle LIM protein, Mlp84B, cooperates with D-titin to maintain muscle structural integrity". Journal of Cell Science 120 (Pt 12): 2066–77. June 2007. doi:10.1242/jcs.000695. PMID 17535853. 
  25. ↑ "Drosophila melanogaster muscle LIM protein and alpha-actinin function together to stabilize muscle cytoarchitecture: a potential role for Mlp84B in actin-crosslinking". Cytoskeleton 70 (6): 304–16. June 2013. doi:10.1002/cm.21106. PMID 23606669. 
  26. ↑ "Specificity of single LIM motifs in targeting and LIM/LIM interactions in situ". Genes & Development 10 (3): 289–300. February 1996. doi:10.1101/gad.10.3.289. PMID 8595880. 
  27. ↑ 27.0 27.1 27.2 "MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure". Cell 88 (3): 393–403. February 1997. doi:10.1016/s0092-8674(00)81878-4. PMID 9039266. 
  28. ↑ "Cardiac Z-disc signaling network". The Journal of Biological Chemistry 286 (12): 9897–904. March 2011. doi:10.1074/jbc.R110.174268. PMID 21257757. 
  29. ↑ "The sarcomeric cytoskeleton: who picks up the strain?". Current Opinion in Cell Biology 23 (1): 39–46. February 2011. doi:10.1016/j.ceb.2010.12.001. PMID 21190822. 
  30. ↑ "The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling". Journal of Muscle Research and Cell Motility 30 (5–6): 171–85. 2009. doi:10.1007/s10974-009-9189-6. PMID 19830582. 
  31. ↑ "Genetics of mechanosensation in the heart". Journal of Cardiovascular Translational Research 4 (3): 238–44. June 2011. doi:10.1007/s12265-011-9262-6. PMID 21360311. 
  32. ↑ "Human muscle LIM protein dimerizes along the actin cytoskeleton and cross-links actin filaments". Molecular and Cellular Biology 34 (16): 3053–65. August 2014. doi:10.1128/MCB.00651-14. PMID 24934443. 
  33. ↑ 33.0 33.1 33.2 "Cellular and functional defects in a mouse model of heart failure". American Journal of Physiology. Heart and Circulatory Physiology 279 (6): H3101–12. December 2000. doi:10.1152/ajpheart.2000.279.6.H3101. PMID 11087268. 
  34. ↑ 34.0 34.1 "Hearts of surviving MLP-KO mice show transient changes of intracellular calcium handling". Molecular and Cellular Biochemistry 342 (1–2): 251–60. September 2010. doi:10.1007/s11010-010-0492-8. PMID 20490897. 
  35. ↑ 35.0 35.1 35.2 "Effects of deletion of muscle LIM protein on myocyte function". American Journal of Physiology. Heart and Circulatory Physiology 280 (6): H2665–73. June 2001. doi:10.1152/ajpheart.2001.280.6.H2665. PMID 11356623. 
  36. ↑ "Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice". Cardiovascular Research 65 (2): 411–8. February 2005. doi:10.1016/j.cardiores.2004.10.025. PMID 15639480. 
  37. ↑ "Neuronal expression of muscle LIM protein in postnatal retinae of rodents". PLOS ONE 9 (6): e100756. 2014-06-19. doi:10.1371/journal.pone.0100756. PMID 24945278. Bibcode: 2014PLoSO...9j0756L. 
  38. ↑ "Nociceptive DRG neurons express muscle lim protein upon axonal injury". Scientific Reports 7 (1): 643. April 2017. doi:10.1038/s41598-017-00590-1. PMID 28377582. Bibcode: 2017NatSR...7..643L. 
  39. ↑ "Muscle LIM Protein: Master regulator of cardiac and skeletal muscle functions". Gene 566 (1): 1–7. July 2015. doi:10.1016/j.gene.2015.04.077. PMID 25936993. 
  40. ↑ 40.0 40.1 "Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy". Human Molecular Genetics 17 (18): 2753–65. September 2008. doi:10.1093/hmg/ddn160. PMID 18505755. 
  41. ↑ "Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy". Circulation 107 (10): 1390–5. March 2003. doi:10.1161/01.cir.0000056522.82563.5f. PMID 12642359. 
  42. ↑ "Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy". Clinical and Translational Science 1 (1): 21–6. May 2008. doi:10.1111/j.1752-8062.2008.00017.x. PMID 19412328. 
  43. ↑ 43.0 43.1 "Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis". Molecular Genetics and Metabolism 80 (1–2): 207–15. 2002. doi:10.1016/s1096-7192(03)00142-2. PMID 14567970. 
  44. ↑ "Skeletal muscle repair in a mouse model of nemaline myopathy". Human Molecular Genetics 15 (17): 2603–12. September 2006. doi:10.1093/hmg/ddl186. PMID 16877500. 
  45. ↑ "The differential gene expression profiles of proximal and distal muscle groups are altered in pre-pathological dysferlin-deficient mice". Neuromuscular Disorders 15 (12): 863–77. December 2005. doi:10.1016/j.nmd.2005.09.002. PMID 16288871. 
  46. ↑ "Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation". Human Molecular Genetics 12 (22): 2895–907. November 2003. doi:10.1093/hmg/ddg327. PMID 14519683. 
  47. ↑ "Muscle LIM protein deficiency leads to alterations in passive ventricular mechanics". American Journal of Physiology. Heart and Circulatory Physiology 282 (2): H680–7. February 2002. doi:10.1152/ajpheart.00773.2001. PMID 11788418. 
  48. ↑ "Cardiomyocyte growth and sarcomerogenesis at the intercalated disc". Cellular and Molecular Life Sciences 71 (1): 165–81. January 2014. doi:10.1007/s00018-013-1374-5. PMID 23708682. 
  49. ↑ 49.0 49.1 "Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice". Journal of Molecular and Cellular Cardiology 63: 155–64. October 2013. doi:10.1016/j.yjmcc.2013.07.016. PMID 23920331. 
  50. ↑ 50.0 50.1 "Calcineurin protects the heart in a murine model of dilated cardiomyopathy". Journal of Molecular and Cellular Cardiology 48 (6): 1080–7. June 2010. doi:10.1016/j.yjmcc.2009.10.012. PMID 19854199. 
  51. ↑ "Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy". Cell 99 (3): 313–22. October 1999. doi:10.1016/s0092-8674(00)81662-1. PMID 10555147. 
  52. ↑ "Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice". Proceedings of the National Academy of Sciences of the United States of America 95 (12): 7000–5. June 1998. doi:10.1073/pnas.95.12.7000. PMID 9618528. Bibcode: 1998PNAS...95.7000R. 
  53. ↑ "Angiotensin II type 1a receptor signals are involved in the progression of heart failure in MLP-deficient mice". Circulation Journal 71 (12): 1958–64. December 2007. doi:10.1253/circj.71.1958. PMID 18037754. 
  54. ↑ "Deletion of Drosophila muscle LIM protein decreases flight muscle stiffness and power generation". American Journal of Physiology. Cell Physiology 301 (2): C373–82. August 2011. doi:10.1152/ajpcell.00206.2010. PMID 21562304. 
  55. ↑ "The Drosophila muscle LIM protein, Mlp84B, is essential for cardiac function". The Journal of Experimental Biology 211 (Pt 1): 15–23. January 2008. doi:10.1242/jeb.012435. PMID 18083727. 

External links




Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:CSRP3&oldid=2253679"