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Group:MUZIC:MLP
From Proteopedia
Cystein and glycine-rich protein 3 (CSRP3)
IntroductionThe 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 AnnotationCSRP3 comprises 194 aminoacids with two 52 residue LIM domains. Each of them is followed by glycine reach sequences of about 10-20 residues UNIPROT (CSRP3_HUMAN). StructuresLIM 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 InteractionsAll 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 CSRP3 with telethonin has been reported previously[2], [3], however recent reports demonstrate that this interaction is not existing [4]. CSRP3 is mainly interacting with α-actinin 2 as well as has 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 in the sarcomere. During myofibrilogenesis CSRP3 has been suggested to form complexes with the muscle helix-loop-helix transcription factors MyoD, MRF4 and myogenin [5]. PathologyMutations 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 [6]. 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 [7]. However a more recent report demonstrates that the W4R mutation is not sufficient to cause DCM [8]. References
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