Group:MUZIC:Titin: Difference between revisions
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Thickness of Z-discs varies significantly between different types of muscles due to adaptation to different levels of mechanic stress. A hypothesis that ascribes titin, particularly it’s Z-repeats, role of the Z-disc thickness determinant, was proposed. It was grounded on the fact that number of repeats and layers in Z-disc correlate ( i.e. sarcomeres with full range of Z-repeats have the thickest disc). However, given idea remains dubious, since it has been found that length of a single repeat is less that thickness of single layer inside Z-disc (19 nm) and thus periodicity cannot be directly determined in proposed way. <br/> | Thickness of Z-discs varies significantly between different types of muscles due to adaptation to different levels of mechanic stress. A hypothesis that ascribes titin, particularly it’s Z-repeats, role of the Z-disc thickness determinant, was proposed. It was grounded on the fact that number of repeats and layers in Z-disc correlate ( i.e. sarcomeres with full range of Z-repeats have the thickest disc). However, given idea remains dubious, since it has been found that length of a single repeat is less that thickness of single layer inside Z-disc (19 nm) and thus periodicity cannot be directly determined in proposed way. <br/> | ||
It is also necessary to mention another noncanonical function of NH2-terminus of titin. Comprehensive studies of mammalian cell cultures provided facts that give a solid proof of nuclear localization of amino-terminal region of titin. Immunostaining coupled with fluorescence microscopy has shown that Z1-Z2-Zr moiety of titin is, indeed, transported into nucleus. A functional nuclear localization signal (NLS) 200-PAKKTKT-206 was discovered by screening of titin constructs of various length. Given NLS enables transport of titin N-terminal domain to the nucleus. This finding was confirmed in following cell lines: human MG-63 and BHK-21, mouse MC3T3-E1, COS-7. It was shown that mutation (Lysin203 to Alanine) in this region leads to the loss of NLS’ function and results in cytoplasmic localization of Z1-Z2-Zr. <br/> In contrast to sarcomeres, titin doesn’t form an ordered network of fibrils, but has rather a “punctate pattern” of distribution both in nucleus and cytoplasm. Using human osteoblast cells, MG-63, it was shown that overexpression of titin Z1-Z2-Zr domain leads to change of cell shape (from spindle-like to rounded), decreases contact inhibition of cells and facilitates cell. Proposed mechanism of action is by activation of Wnt/β-catenin pathway. This signaling cascade is important for proper bone maintenance, Z1-Z2-Zr part of titin may participate in remodeling of bone tissue. <ref> Nuclear localization of the titin Z1Z2Zr domain and role in regulating cell proliferation. PMID 18684985 </ref> | It is also necessary to mention another noncanonical function of NH2-terminus of titin. Comprehensive studies of mammalian cell cultures provided facts that give a solid proof of nuclear localization of amino-terminal region of titin. Immunostaining coupled with fluorescence microscopy has shown that Z1-Z2-Zr moiety of titin is, indeed, transported into nucleus. A functional nuclear localization signal (NLS) 200-PAKKTKT-206 was discovered by screening of titin constructs of various length. Given NLS enables transport of titin N-terminal domain to the nucleus. This finding was confirmed in following cell lines: human MG-63 and BHK-21, mouse MC3T3-E1, COS-7. It was shown that mutation (Lysin203 to Alanine) in this region leads to the loss of NLS’ function and results in cytoplasmic localization of Z1-Z2-Zr. <br/> In contrast to sarcomeres, titin doesn’t form an ordered network of fibrils, but has rather a “punctate pattern” of distribution both in nucleus and cytoplasm. Using human osteoblast cells, MG-63, it was shown that overexpression of titin Z1-Z2-Zr domain leads to change of cell shape (from spindle-like to rounded), decreases contact inhibition of cells and facilitates cell. Proposed mechanism of action is by activation of Wnt/β-catenin pathway. This signaling cascade is important for proper bone maintenance, Z1-Z2-Zr part of titin may participate in remodeling of bone tissue. <ref> Nuclear localization of the titin Z1Z2Zr domain and role in regulating cell proliferation. PMID 18684985 </ref> | ||
A list of proteins that directly interact with the Z-disk portion of titin and their functions are given in the table below (cited from minireview of Kruger and Linke, ''2011''. <ref> The giant protein titin: a regulatory node that integrates myocyte signaling pathways PMID: 21257761 </ref>) | A list of proteins that directly interact with the Z-disk portion of titin and their functions are given in the table below (cited from minireview of Kruger and Linke, ''2011''. <ref> The giant protein titin: a regulatory node that integrates myocyte signaling pathways PMID: 21257761 </ref>) | ||
<center> '''Binding partners of titin within Z-disk''' </center> | <center> '''Binding partners of titin within Z-disk''' </center> | ||
