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Polymerization mechanism

Studies of actin have shown that it has many functions within living cells. This range of functions is due to the diverse morphology of its structures and its interactions with actin-binding proteins (ABPs). (Conformational Dynamics of Actin: Effectors and Implications for Biological Function) The diversity in the functional ability of actin proteins is due in part to its interaction with actin-binding proteins. F-actin and G-actin interact with a wide array of proteins. There are over 150 known actin binding proteins (ABPs), which makes up 25% of cellular protein.  (http://www.cytoskeleton.com/actin?gclid=CNyRpoPC3a8CFeUEQAodTFkoCg) Actin has proved to be an important component in the cytoskeleton. The actin cytoskeleton is known as the microfilament and has a multi-purpose role in important cell processes such as maintaining cellular polarity, cell shape, cell motility, adhesion, cytokinesis and endocytosis. (Conformational Dynamics of Actin: Effectors and Implications for Biological Function)  Myosin molecules are a class of actin motors that aid in creating movement by “walking” across actin filaments and contracting muscle tissues. Microfilaments, also known as thin filaments are helical polymers composed of globular actin (G-actin). The polymers are polar and bind to nucleotides such as ATP in order to hydrolyze them. (Walter F., PhD. Boron (2003) Medical Physiology: A Cellular And Molecular Approaoch Elsevier/Saunders, pp. 1,300 ISBN:1-4160-2328-3. Page 28) Actin has no important enzymatic activity, however, it inhibits DNase I and activates the myosin ATPase. Actin filaments activate the Mg2+ ATPase activity and the movement of myosin along actin filaments produces the force for muscle contraction and other cell movements. Motility mechanisms which involve actin are controlled by the interaction in the G or F form with the various ABPs. (Structure and Function of Actin by Wolfgang Kabsch)  

Many of the functions of the cytoskeleton involve cytoskeleton and plasma membrane interactions. Proteins that exist between the two help to control cell shape, define the membrane domains and regulate cell/cell interactions and adhesion. There are at least 15 major protein species involved in the membrane-cytoskeleton of the human red blood cell. A mutation in any of these proteins can lead to cell fragility and cell death. Homologs of the erythrocyte membrane-skeleton can be found in many other cell types, which suggests the significance of these proteins. One of particular importance is the actin associated protein dystrophin. Dystrophin is an important part of the sarcolemmal membrane where it links the membrane to the sides of the actin filament bundles. Mutations in this protein leads to muscular dystrophies such as Duchenne’s disease or Becker muscular dystrophy. A homolog of dystrophin called utropin is thought to play a similar role in non-muscle cells.(http://www.cytoskeleton.com/actin?gclid=CNyRpoPC3a8CFeUEQAodTFkoCg)

   The genome of many mammals, including humans contains six actin genes, ACTA1, ACTA2, ACTB, ACTC, ACTG1 and ACTG2. Four of these are differentially expressed in cardiac (ACTC), smooth (ACTA2) enteric (ACTG2) and skeletal muscles (ACTA1); two are described as cytoplasmic actin genes (ACTB and ACTG1) and are expressed in all cells.  (Actin-Binding Proteins and Disease ) Actin mutations were not really known until the last 6-10 years. Mutations that have been found to cause human diseases have been found in the ACTC cardiac muscle gene which can cause dilated or hypertrophic cardiomyopathies including congenital fiber-type disproportion (CFTDP). Recently, mutations in ACTG1 have been associated with autosomal dominant deafness. Majority of actin disease mutations have been found to be dominant mutations. This has been the case for actin mutations is the Drosophila flight muscle-specific actin gene ACT88F. Scientists believe the common dominance of actin mutations is because the major functions of actin occur when it is in its F-form, associated with other proteins. The dominant actin mutations that lead to disease are mostly missense mutations. Actin mutations have been found in a variety of species such as yeast, nematodes and flies whose genomes are more accessible to mutagenesis. It is thought that there are three reasons why actin mutations are likely to be at very low frequencies in human populations: 1. actin is a ubiquitously expressed protein, 2. it is a highly conserved protein with many binding partners, so mutations in a large fraction of actin residues appear to cause a severe phenotype in humans and other organisms and 3. most actin mutations are dominant and given the usually severe effects, are not passed on to offspring. Thus familial actin mutants are likely to be relatively mild dominant alleles or recessive. Severe dominant alleles are likely to be de novo mutations. In the case of cytoplasmic actin, five ACT1G disease-causing mutant alleles are known so far and no disease-causing ACTB alleles have yet been described.

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