Myosin-binding protein

The cytoskeleton also contains different accessory proteins, which, in accordance with their affinities and functions, are designated as microtubule-associated proteins (MAPs), actin-binding proteins (ABPs), intermediate-filament-associated proteins (IFAPs), and myosin-binding proteins. This chapter is focused on those parts of the cytoskeleton that are composed of microfilaments and microtubules and their associated proteins. The subject of intermediate filaments is dealt with in detail in Volume 2. 

Figure 49-13. Simplified scheme of the causation of familial hypertrophic cardiomyopathy (MIM 192600) due to mutations in the gene encoding fi-myosin heavy chain. Mutations in genes encoding other proteins, such as the troponins, tropomyosin, and cardiac myosin-binding protein C can also cause this condition. Mutations in genes encoding yet other proteins (eg, dystrophin) are involved in the causation of dilated cardiomyopathy.

Current evidence indicates that PLN phosphorylation appears to be dominant over troponin I phosphorylation (Li, et al., 2000). The faster SR Ca uptake by phospho-rylated PLN also contributes to increased SR Ca load, which is available for subsequent release, resulting in an inotropic effect. The increased ICa by PKA activation also contributes to the inotropic effects of the (i-AR agonists. The myofilament effects of PKA appear to be almost entirely attributable to troponin I phosphorylation (vs. myosin binding protein C) because substitution of troponin I with a non-phosphorylatable troponin I abolishes myofilament effects of PKA (Kentish, et al., 2001 Pi, et al., 2002). 

Also in the A-band, in the middle of each of the bridge regions, the myosin filaments carry the extra protein originally known as C-protein (now often called myosin-binding protein G MyBP-C Offer et al, 1973), which occurs in two sets of 7 to 9 stripes in the G-zones in each half of the A-band (Fig. 5C Bennett et al, 1986 Sjostrom and Squire, 1977). The structure, interactions, and role of G-protein are discussed in Section IV.C. 

Kunst, G., Kress, K. R., Gruen, M., Uttenweiler, D., Gautel, M., and Fink, R. H. (2000). Myosin binding protein C, a phosphorylation-dependent force regulator in muscle that controls the attachment of myosin heads by its interaction with myosin S2. Circ. Res. 86, 51-58. 

Moolman-Smook, J., Flashman, E., De Lange, W., Li, Z., Corfield, V., Redwood, C., and Watkins, H. (2002). Identification of novel interactions between domains of myosin binding protein-C that are modulated by hypertrophic cardiomyopathy missense mutations. Circ. Res. 91, 704-711. 

The thick filament system, which comprises myosin protein, connected from the M-line to the Z-disc by titin (connectin), and myosin-binding protein C, which binds at one end to the thick filament and at the other to actin. 

Dyspnea, chest pain or syncope, usually features ventricular hypertrophy with impingement on LV volume and often LV outflow obstruction. Most cases hereditary, but some are new mutations. Defective genes for/3-MHC, either MLC, TnT, Tnl, a-tropomyosin, myosin binding protein C. 

The genetic predisposition to HCM is thought to be an autosomal dominant trait with variable penetrance. Owing to the wide variability of presentation, not aU cases in a family may be detected. HCM usually is caused by mutations in the genes for -myosin heavy chain, myosin-binding protein C, and cardiac troponin... 

These two phenotypes of smooth muscle, in addition to having marked differences in contractile activity, express different isoforms of several contractile proteins and certain soluble enzymes. In particular, proliferative smooth muscle contains at least three PDPKs p34 i 2 p42 , and p44 PK the contractile phenotype of smooth muscle, only p42 P and p44 mark have been identified. The precise function and a complete description of the substrates for MAPK in the contractile phenotype of smooth muscle are unknown however, one substrate that has been idenhfied is the actin and myosin binding protein, caldesmon. Because of the phosphorylation of cal-desmon, MAPK may be involved in either smooth muscle contractile regulation or the structural organization of actin filaments within smooth muscle cells. 

The nucleation of thaumalin, trypsin, lobster a-crustatyanin, lysozyme, c-phycocyanin, myosin-binding protein-C, and a-actinin actin binding is aihanced in the presence of a porous medium nonporous surfaces are less successful at promoting nucleation (Chayen et al. 2006). Monte Carlo simulations confirmed that nucleation out of a filled pore is always faster than on a perfectly smooth surface, and the log of the rate varies almost linearly with pore size (Page and Sear 2006). 

Shaffer JF, Kensler RW, and Harris SP. The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner. Journal of Biology Chemistry 2009 284 12318-27. 

The leucine zipper DNA-binding proteins, described in Chapter 10, are examples of globular proteins that use coiled coils to form both homo- and heterodimers. A variety of fibrous proteins also have heptad repeats in their sequences and use coiled coils to form oligomers, mainly dimers and trimers. Among these are myosin, fibrinogen, actin cross-linking proteins such as spectrin and dystrophin as well as the intermediate filament proteins keratin, vimentin, desmin, and neurofilament proteins. 

Approximately 500 of the 820 amino acid residues of the myosin head are highly conserved between various species. One conserved region, located approximately at residues 170 to 214, constitutes part of the ATP-binding site. Whereas many ATP-binding proteins and enzymes employ a /3-sheet-a-helix-/3-sheet motif, this region of myosin forms a related a-f3-a structure, beginning with an Arg at (approximately) residue 192. The /3-sheet in this region of all myosins includes the amino acid sequence... 

The Role of Myosins in Cell Locomotion The Role of Actin-Binding Proteins in Cell Locomotion The Transduction of Extracellular Motility Signals to the Cytoskeleton Lipid Flow and Cell Locomotion The Role of Cell Locomotion in Metastasis Intracellular Motility Microtubule-Based Intracellular Motility... 

In striated muscle, there are two other proteins that are minor in terms of their mass but important in terms of their function. Tropomyosin is a fibrous molecule that consists of two chains, alpha and beta, that attach to F-actin in the groove between its filaments (Figure 49-3). Tropomyosin is present in all muscular and muscle-fike structures. The troponin complex is unique to striated muscle and consists of three polypeptides. Troponin T (TpT) binds to tropomyosin as well as to the other two troponin components. Troponin I (Tpl) inhibits the F-actin-myosin interaction and also binds to the other components of troponin. Troponin C (TpC) is a calcium-binding polypeptide that is structurally and functionally analogous to calmodulin, an important calcium-binding protein widely distributed in nature. Four molecules of calcium ion are bound per molecule of troponin C or calmodulin, and both molecules have a molecular mass of 17 kDa. 

Troponin C Regulates muscle contraction complex formation triggers actin to realign and interact with myosin (389,390) — inhibited by relaxins, which are themselves Ca2+-binding proteins (v.s.)... 

GFP hopo ICBP IP3 Ln3+ mal memal MLCK nota oxine par pdta pmea py quin-2 green fluorescent protein hydroxypyridinon(at)e intestinal calcium-binding protein inositol 1,4,5-triphosphate a lanthanide(III) cation malonate methylmalonate myosin light chain kinase 1,4,7-triazacyclononane-l,4,7-triacetate 8- hydroxyquinoline pyridine-2-azo-4 -dimethylaniline propylene-1,2-diaminetetraacetate 9- [2-(phosphonomethoxy)ethyl] adenine pjrridine pjrridyl 8-amino-2- [(2-amino-5-methylphenoxy )methyl] -6-methoxyquinoline-ATJV -tetraacetate 2- [ [2-[his(carboxymethyl)amino]-5-methyl-phenoxy] methyl] -6-methoxy-8- [bis(carboxymethyl) amino] quinoline]... 

Assembly of the actin network merely by interaction with these binding proteins can itself account for pseudopodia formation and propulsive movement. However, there is some evidence to suggest that F-actin-myosin interactions are required for vectorial movement hence it has been demonstrated that pseudopodia contain filament networks comprising actin and myosin. Myosin plays a role in the contractile movement of neutrophils in a... 

Tropomyosin is a fibrous molecule which twists around the F-actin strands. The troponin (Tn) complex is composed of three proteins Tnl (I = inhibitory) which prevents myosin binding to actin in the resting muscle, TnT which binds tropomyosin and TnC (C for calcium-binding). Cardiac muscle troponins are different from those of skeletal muscle and are designated cTnl, cTnT and cTnC. 

ATP is used not only to power muscle contraction, but also to re-establish the resting state of the cell. At the end of the contraction cycle, calcium must be transported back into the sarcoplasmic reticulum, a process which is ATP driven by an active pump mechanism. Additionally, an active sodium-potassium ATPase pump is required to reset the membrane potential by extruding sodium from the sarcoplasm after each wave of depolarization. When cytoplasmic Ca2- falls, tropomyosin takes up its original position on the actin and prevents myosin binding and the muscle relaxes. Once back in the sarcoplasmic reticulum, calcium binds with a protein called calsequestrin, where it remains until the muscle is again stimulated by a neural impulse leading to calcium release into the cytosol and the cycle repeats. 

The calcium mediated contraction of smooth muscle, which unlike striated muscle does not contain troponin, is quite different and requires a particular calcium-binding protein called calmodulin. Calmodulin (CM) is a widely distributed regulatory protein able to bind, with high affinity, four Ca2+ per protein molecule. The calcium—calmodulin (CaCM) complex associates with, and activates, regulatory proteins, usually enzymes, in many different cell types in smooth muscle the target regulatory proteins are caldesmon (CDM) and the enzyme myosin light chain kinase (MLCK). As described below, CaCM impacts on both actin and myosin filaments. 

Flavonoids are known to inhibit the function of many ATP-binding proteins, such as mitochondrial ATPase, myosin, Na/K and Ca plasma membrane ATPases, protein kinases, topoisomerase II, and multidrug resistance (MDR) proteins. In general, inhibition takes place through binding of the flavonoids to the ATP-binding site. Only two cases relevant to the inhibition of carcinogenesis by flavonoids" " will be discussed in detail. 

A primary function of the SH3 domains is to form fimctional oligomeric complexes at defined subcellular sites, frequently in cooperation with other modular domains. SH3 domains are foimd in many proteins associated with the cytoskeleton or with the plasma membrane. Examples are the actin binding protein a-spectrin and myosin lb. Furthermore, SH3 interactions are involved in signal transduction in the Ras pathway (see Chapter 9). 

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