Group:MUZIC:MLP

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Cystein and glycine-rich protein 3 (CSRP3)

Introduction

The Cystein and glycine-rich protein 3 (CSRP3), or as also known as Muscle LIM Protein (MLP), Cardiac LIM protein, or Cysteine-rich protein 3 (CRP3), is one of the three CSRP family members identified in vertebrates. CSRP3 has been identified muscle and cardiac cells[1]. The three family members contain 192-194 residues and two LIM domains adjacent to a flexible glycine-rich linker. Each LIM domain comprises two Zn-binding motifs CCHC and CCCC representing a structural and presumably functional independent unit.

Sequence Annotation

CSRP3 comprises 194 amino acids with two 52 residue LIM domains. Each of them is followed by glycine-rich sequences of about 10-20 residues UNIPROT (CSRP3_HUMAN).

Structures

Solution structure of the C-terminal LIM domain of MLP/CSRP3 (PDB entry: 2o13 ), Colour code: blue: N-term, red: C-term

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Solution structure of the N-terminal LIM domain of MLP/CSRP3 (PDB entry: 2o10 ), Colour code: blue: N-term, red: C-term

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LIM domains have been intensively characterized using NMR. The two LIM domains of CSRP3 have been determined by NMR (LIM1: 2O10 and LIM2: 2O13 )

Function and Interactions

All three CSRPs are associated with the actin cytoskeleton and have similar functions in different muscle types. They up-regulate the myogenesis and have specific roles in the organisation of cytosolic structures in cardiomyocytes. It was also suggested that CSRPs may have a role in stretch sensing[2]. MLP (CSRP3) is localized mainly in the Z-disc and the M-band of the striated muscle[3]. Within the Z-disc, the interactions of CSRP3 with telethonin and α-actinin2 have been reported previously[2][4][5], a more recent report however underscoring the role of CSRP3 as a scaffold protein[6]. CSRP3 has also been suggested to interact with βI-spectrin, N-RAP (Nebulin-related-anchoring protein) and cofilin2 (CFL2), underlying the essential role of CSRP3 as a scaffold protein. During myofibrilogenesis CSRP3 has been proposed to form complexes with the muscle helix-loop-helix transcription factors MyoD, MRF4 and myogenin [6]. Finally, it is involved in the anchorage of calcineurin to the Z-disc[7].

Pathology

CSRP3(MLP) has been inmplicated in two types of hereditary cardiomyopathies, hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Familial HCM is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death [8]. Mutations in the first LIM domain have been linked to HCM and allll of them (L44P, S54R, E55G, C58G) are related to the proper binding of Zinc to the protein, thus causing conformational alterations. Dilated cardiomyopathy (DCM) is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia and patients have the risk of premature death [2]. The mutation W4R in CSRP3 has been reported to cause dilated cardiomyopathy (DCM) of type 1Mv. However in more recent reports there is the suggestion that this allelic variant might actually be a common polymorphism [6][9].

References

  1. ↑ Fung YW, Wang RX, Heng HH, Liew CC. Mapping of a human LIM protein (CLP) to human chromosome 11p15.1 by fluorescence in situ hybridization. Genomics. 1995 Aug 10;28(3):602-3. PMID:7490106 doi:http://dx.doi.org/10.1006/geno.1995.1200
  2. ↑ 2.0 2.1 2.2 Knoll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002 Dec 27;111(7):943-55. PMID:12507422
  3. ↑ Flick MJ, Konieczny SF. The muscle regulatory and structural protein MLP is a cytoskeletal binding partner of betaI-spectrin. J Cell Sci. 2000 May;113 ( Pt 9):1553-64. PMID:10751147
  4. ↑ Zou P, Pinotsis N, Lange S, Song YH, Popov A, Mavridis I, Mayans OM, Gautel M, Wilmanns M. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature. 2006 Jan 12;439(7073):229-33. PMID:16407954 doi:10.1038/nature04343
  5. ↑ Louis HA, Pino JD, Schmeichel KL, Pomies P, Beckerle MC. Comparison of three members of the cysteine-rich protein family reveals functional conservation and divergent patterns of gene expression. J Biol Chem. 1997 Oct 24;272(43):27484-91. PMID:9341203
  6. ↑ 6.0 6.1 6.2 Geier C, Gehmlich K, Ehler E, Hassfeld S, Perrot A, Hayess K, Cardim N, Wenzel K, Erdmann B, Krackhardt F, Posch MG, Osterziel KJ, Bublak A, Nagele H, Scheffold T, Dietz R, Chien KR, Spuler S, Furst DO, Nurnberg P, Ozcelik C. Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Hum Mol Genet. 2008 Sep 15;17(18):2753-65. Epub 2008 May 27. PMID:18505755 doi:10.1093/hmg/ddn160
  7. ↑ Heineke J, Ruetten H, Willenbockel C, Gross SC, Naguib M, Schaefer A, Kempf T, Hilfiker-Kleiner D, Caroni P, Kraft T, Kaiser RA, Molkentin JD, Drexler H, Wollert KC. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1655-60. Epub 2005 Jan 21. PMID:15665106 doi:10.1073/pnas.0405488102
  8. ↑ Geier C, Perrot A, Ozcelik C, Binner P, Counsell D, Hoffmann K, Pilz B, Martiniak Y, Gehmlich K, van der Ven PF, Furst DO, Vornwald A, von Hodenberg E, Nurnberg P, Scheffold T, Dietz R, Osterziel KJ. Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy. Circulation. 2003 Mar 18;107(10):1390-5. PMID:12642359
  9. ↑ Hoshijima M, Knoll R, Pashmforoush M, Chien KR. Reversal of calcium cycling defects in advanced heart failure toward molecular therapy. J Am Coll Cardiol. 2006 Nov 7;48(9 Suppl 1):A15-23. PMID:17084280 doi:10.1016/j.jacc.2006.06.070

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Nikos Pinotsis

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