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In 1942, [http://en.wikipedia.org/wiki/Brun%C3%B3_Ferenc_Straub Bruno Ferenc Straub] isolated actin as a water soluble component of muscle acetone powder. He found that at increased ionic strength the G-actin molecules would come together to form the F-actin filament. Actin was later found in non-muscle cells and its structure was seen through the use of [http://en.wikipedia.org/wiki/Immunofluorescence_microscopy immunofluorescence microscopy]. The next major accomplishment came with the discovery of the amino acid sequence. This allowed researchers to locate chemical and enzymatic alterations and to study how they affected the properties of the molecule. The high conservation of actin’s structure throughout various species was discovered through [http://en.wikipedia.org/wiki/Immunofluorescence_microscopy comparative sequence analysis]. In 1950, Straub reported that actin contained bound ATP and that during the polymerization of the monomers into microfilaments, the ATP was hydrolyzed to ADP and inorganic phosphate. (Straub FB, Feuer G (1989). "Adenosinetriphosphate. The functional group of actin. 1950". Biochim. Biophys. Acta 1000: 180–95.PMID 2673365.) His discovery led to his suggestion that ATP-bound actin transforming into ADP-bound actin was what created muscle contractions. In the early 1980’s the principles of actin polymerization were exposed and the first actin-binding proteins (ABPs) were characterized according to their in vivo and in vitro functions. In 1990, the crystal structure of G-actin was solved by Kabsch. (Kabsch W, Mannherz HG, Suck D, Pai EF, Holmes KC (September 1990). "Atomic structure of the actin:DNase I complex". Nature 347 (6288): 37–44. doi:10.1038/347037a0. PMID 2395459.) In this same year a model of F-actin was suggested by Holmes et al. The model was created by fitting a helix of G-actin structures according to low-resolution fiber diffraction data from the F-actin. ( Holmes KC, Popp D, Gebhard W, Kabsch W (September 1990). "Atomic model of the actin filament". Nature 347 (6288): 44–9.doi:10.1038/347044a0. PMID 2395461.) Further advances in cryoelectron microscopy allowed scientists to find the binding sites for myosin and tropomyosin. A combination of [http://en.wikipedia.org/wiki/X-ray_crystallography X-ray crystallography] with fiber diffraction led to an atomic model of F-actin. (Structure and Function of Actin by Wolfgang Kabsch) After some debate actin also became generally accepted as an important structural and functional component of the cell nucleus (Conformational Dynamics of Actin: Effectors and Implications for Biological Function) Since this pioneering work by Straub, interest in actin has increased tremendously and so has the realization of how complex its structure is.

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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