Group:MUZIC:MLP

Introduction

The Cystein and glycine-rich protein 3 (CSRP3), or as also known as Muscle LIM Protein (MLP), 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 aminoacids with two LIM domains followed by glycine reach sequences Pubmed (CSRP3_HUMAN).

Structures

LIM domains have been intensively characterized using NMR. The two LIM domains of CSRP3 have been also 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 varieties. CSRP3 is localized in Z and M-lines in striated muscles. The interactions of MLP with telethonin has been reported previously^[2], ^[3], however recent reports demonstrate that this interaction is not existing ^[4].

βI-spectrin, N-RAP (Nebulin-related-anchoring protein) and cofilin2 (CFL2) have been suggested in the literature, underlying the essential role of MLP as a scaffold protein in the sarcomere. During myogenesis MLP has been suggested to form complexes with the muscle helix-loop-helix transcription factors MyoD, MRF4 and myogenin.

Pathology

Mutations on the first LIM domain have been linked to familial hypertrophic cardiomyopathy (HCM). All of them (L44P, S54R, E55G, C58G) are related to the proper binding of Zinc to the protein, thus causing conformational alterations. Familial hypertrophic cardiomyopathy 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 ^[5]. The mutation W4R in CSRP3 has been reported to cause dilated cardiomyopathy of type 1Mv(DCM). Dilated cardiomyopathy 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 ^[6]. However a more recent report demonstrates that the W4R mutation is not sufficient to cause DCM ^[7].

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. ↑ 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. ↑ PIMD: 16407954
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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

Additional References

• Gehmlich K, Ehler E, Perrot A, Furst DO, Geier C. "MLP: A Stress Sensor Goes Nuclear" by Sylvia Gunkel, Jorg Heineke, Denise Hilfiker-Kleiner, Ralph Knoll, J Mol Cell Cardiol. 2009;47(4):423-5. J Mol Cell Cardiol. 2010 Feb;48(2):424-5; author reply 426-7. Epub 2009, Oct 30. PMID:19879879 doi:10.1016/j.yjmcc.2009.10.021
• Gehmlich K, Geier C, Milting H, Furst D, Ehler E. Back to square one: what do we know about the functions of muscle LIM protein in the heart? J Muscle Res Cell Motil. 2008;29(6-8):155-8. Epub 2008 Dec 30. PMID:19115046 doi:10.1007/s10974-008-9159-4
• Knoll R, Kostin S, Klede S, Savvatis K, Klinge L, Stehle I, Gunkel S, Kotter S, Babicz K, Sohns M, Miocic S, Didie M, Knoll G, Zimmermann WH, Thelen P, Bickeboller H, Maier LS, Schaper W, Schaper J, Kraft T, Tschope C, Linke WA, Chien KR. A common MLP (muscle LIM protein) variant is associated with cardiomyopathy. Circ Res. 2010 Mar 5;106(4):695-704. Epub 2009 Dec 31. PMID:20044516 doi:10.1161/CIRCRESAHA.109.206243
• Schallus T, Edlich C, Stier G, Muhle-Goll C. 1H, 13C, and 15N assignment of the muscular LIM protein MLP/CRP3. Biomol NMR Assign. 2007 Jul;1(1):41-3. Epub 2007 May 10. PMID:19636821 doi:10.1007/s12104-007-9010-7
• 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