Chapter 4: PRINCIPLES OF MOLECULAR CARDIOLOGY CYTOSKELETAL PROTEINS
The cell cytoskeleton refers to the fibrous proteins that are present in the cytoplasm. The cytoskeletal fibers give the cell strength and rigidity and control movement within the cell. For example, the microtubules provide the tracks along which vesicles are transported by tubulin-binding molecules. These cytoskeletal proteins form three major classes subdivided according to size into microfilaments,42 microtubules, and intermediate filaments.43 The microfilaments are polymers of the protein subunit actin; the microtubules are polymers of the subunits of G- and P-tubulin, and the intermediate filaments are polymers of five different rod-shaped protein subunits. The polymerization and depolymerization of these fibers are closely regulated by the cell. Just as FHCM is essentially a sarcomeric disease, it appears that familial dilated cardiomyopathy (FDCM) is a disease of cytoskeletal proteins. Mutations in dystrophin,44 Ot-dystroglycan,44 0(-sarcoglycan,45 metavinculin,46 actin,47 and desmin48 have all been shown to be associated with FDCM.
In addition to the actin thin filaments of the sarcomere, which help to generate the force of contraction, actin filaments are distributed throughout the cytoplasm of essentially all cells and serve to transmit force. To serve its role as a transmitter of force, actin is linked to several other proteins. The dual function of actin is exemplified in the thin sarcomere filaments that generate force by mutations that induce FDCM,47 whereas other mutations in the portion of the molecule that transmits force induce FHCM.49 Titan, which binds myosin to the Z-line, is essential to the velocity and force developed by myosin-actin interaction, as is nebulin, which attaches actin to the Z-line. Dystrophin is the protein encoded by the gene responsible for Duchenne muscular dystrophy and is known to be a subsarcolemmal protein with the function of anchoring actin to the plasma membrane. Spectrin, which binds actin to the plasma membrane, has several isoforms, one of which is specific to the heart.50
Microtubules are about 24 nm in diameter, varying widely in length from a fraction of a micrometer to tens of micrometers. The microtubule wall is made up of globular subunits about 4 to 5 nm in diameter, and these subunits are arranged in 13 longitudinal rows encircling the hollow-appearing center. This basic design is present in practically all microtubules. Colchicine, which inhibits microtubule assembly, does so by binding to the tubulin. Microtubules are involved in movement and organization of cell organelles.
In contrast to actin and tubulin, which are widely distributed among cell types, the rather insoluble intermediate filaments are tissue- and cell-specific. Actin and tubulin are globular, and the polymers they form are rather like beads on a string. In contrast, intermediate filament subunit proteins are extended molecules that form ropelike polymers. The intermediate filament proteins include desmin, vimentin, neurofilaments, glial fibrillary acid protein, and the keratins. In cardiac myocytes, desmin filaments connect the desmosomes from one muscle cell to another and form the scaffold for both the Z-disk and the myofibrils. The desmin filament plays a role in the transmission of the stress and strain of contractile force between cardiac myocytes. It also connects the nucleus to the plasma membrane. Recently, it was shown that a mutation in the tail region of desmin causes FDCM.48 Mutations in the rod region induce a phenotype exhibiting skeletal and cardiac manifestations, whereas mutations in the tail region exhibit only a cardiac phenotype.48 The restriction of the phenotype to cardiac tissue suggests a specific cardic function for the tail domain.
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