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CapZ, also known as β-actinin and, in non-muscle cells, capping protein, is an actin-binding protein that inhibits the elongation of filamentous actin [10] [27] [28]. The regulation of the dynamic properties and organization of actin filaments is critical in the regulation of a variety of important biological processes such as developmental organization of tissues and cells, cell motility and phagocytosis [16] [28].

History
In his 1887 paper, Halliburton described a substance, “myosin ferment”, that appeared to be responsible for the coagulation of myosin in muscle extracts. It was not until 1942, however that Bruno Straub was able to isolate and this protein that he named actin (for its activation of myosin) in muscle. Because this research was done in Hungary in the midst of the Second World War the findings were only published in local periodicals [22]. The discovery of actin was then followed by discovery of many actin-binding proteins (ABPs) which collectively regulate actin and produce the diverse range of conformations and functions of actin within different types of cells [16].

Capping proteins, also known as end-blocking proteins are a class of ABP that bind, or “cap” the either the barbed (+) or pointed (-) end of actin [23]. A type of capping protein, named capping protein, was first isolated by Isenberg in 1980 [8] and it has since been found to be a barbed end (+)-binding protein that is highly conserved and ubiquitous in eukaryote cells [19] [26]. Capping protein that is found in muscle is known as either beta-actinin [26] or CapZ due to its location in the z-line [3].

Genetics
The two subunits of CapZ are encoded for by three genes, located at different loci. Cap Z α1 and β are both located on Chromosome 1, the largest chromosome in the Human genome. Cap Z α2 is found on chromosome 7 [11] [12] [13]. CapZ α1 is a gene of about 52 kilo basepairs, with 10 exons, making the coding strand (mRNA) used in translation about 851 nucleotides in length [11]. CapZ α2 is larger than the α2 gene, at about 56 kilo basepairs, again with 10 exons. This creates a coding strand of about 950 nucleotides [12]. CapZ β is the largest gene, at about 80 kilo basepairs, with 10 exons. The coding strand of approximately 800 nucleotides long [13]. The nascent polypeptides translated from all three genes are roughly the same length. All three genes are highly conserved across a wide range of species, from humans (Homo Sapiens), to rice (O.sativa)[11] [12] [13], due to its importance in cell movement, division, and formation of the cytoskeleton. Several pseudogenes are also found in various loci in the human genome [11]. A third gene of CapZ α is found in the male germ cell-line.

Structure
Capping protein is highly conserved and ubiquitous among eukaryotes. CapZ has an elongated structure with the approximate dimensions of 90 x 50 x 50 Å [28]. It is a heterodimer composed of closely assembled of α and β subunits. Although the primary structure of the subunits is not homologous, they appear almost identical and this generates a pseudo 2-fold rotational symmetry. The α and β subunits interact via hydrophobic residues and are tightly bound resulting in a stable structure. Each of the CapZ subunits can bind to one actin with its respective C-terminal. This corresponds with the dimeric structure of filamentous actin. There are other regions in the C-terminal domains could also contribute to actin binding but little is currently known about these [28]. In vertebrates, two isoforms of the β subunit are found. The β1 subunit is primarily found in the sarcomeres of muscle cells whereas the β2 subunit is found in non-muscle cells. The subunits have been found to differ by 30 amino acids at the actin-binding carboxy terminal. The physiological significance of this difference has yet to be determined [20].

Actin binding (capping)
Actin filaments have two ends that capping proteins can bind to. These are the barbed (+) end and pointed (-) end [19]. The barbed (+) end is primarily a site of actin monomer assembly while the pointed (-) end is a site of monomer loss, or disassembly. Cap Z binds to the barbed (+) end of actin filaments and thus inhibits further elongation of the actin filament [16]. CapZ is also important in the nucleation of actin polymers [14] [19] [28].

Function in muscles
The CapZ stabilization of actin filaments is very important in sarcomeres. CapZ is anchored to the Z-line of sarcomeres through interactions with titin and α-actinin [14] [21]. It is important for the structural integrity of the sarcomere because it anchors the thin filaments of the sarcomere (actin) in the Z-lines and regulates their length [14] [19]. CapZ is also important in the process of development. During myofibrillogenesis CapZ is found in developing Z-discs before the organization of actin. This indicates that it acts as a target molecule for actin and directs the process of actin filament assembly [19].

Regulating proteins
There are several proteins that mediate the activity of Capz. The primary signalling pathway appears to involve PIP2 as a second messenger and protein kinase C (PKC). The PIP2 and PKC pathways cause CapZ to rapidly dissociate with actin. This destabilizes the barbed (+) end and permits actin polymerization [20].

There are other molecules that act on the barbed end of filamentous actin. Formins and Ena/VASP molecules also act antagonistically to CapZ. Formins compete with cap Z and other tight capping proteins to bind to the barbed (+) end of actin. Upon binding, they stabilize the actin strand in a similar manner to CapZ, but also allow slow elongation of the actin filament [31]. Ena/VASP also binds to the barbed (+) ends of actin to protect it from binding to cap Z and promote actin filament polymerization [1].

Current Research & Medical Applications
Despite the fact that much of the research characterizing Cap Z was performed in the 1980s and 1990s, research interest in further investigating Cap Z and its interactions with other proteins has been renewed. A few examples of recent research studies and their findings can be found below. In 2008, researchers knocked down the protein nebulin and discovered that its interaction with Cap Z is important for the correct alignment of actin filaments. When nebulin was knocked down, CapZ assembly was reduced and actin filaments were misaligned [15]. Another protein, BAG3 was found in 2010 to be important in preserving the interaction of Cap Z with actin filaments and protecting it from degradation. It was also found that mutations in BAG3 can influence human health and disease, as patients with mutations in the gene for BAG3 are susceptible to cardiac myopathy [7]. So far in 2012, several papers have been published on Cap Z. It was found that another capping protein in slime molds, Cap 32/34 has a very similar structure to Cap Z, despite having low sequence homology. This protein may help to provide a model for the cytoplasmic form of Cap Z, which has thus far been difficult to characterize [4]. Furthermore, CapZ may not only have a structural role – it may also be involved in signal transduction. It has been found that while mice who greatly over or under express CapZ recover worse after an ischemic event, mice who have a small reduction in CapZ protein expression recover better. The mechanism underlying this effect is not known, but may be related to PKC signalling [30]. Earlier this year, researchers studied the effect of CapZ deficiency on the β-adrenergic pathway in heart muscle and found that CapZ deficient mice have hypercontractile hearts. Although activation of the β-adrenergic pathway had a similar affect on wt hearts, the researchers found that the phosphorylation profiles of CapZ-deficient and wild type were different. They suggested that the increased contractility might be due to increased calcium sensitivity in the CapZ deficient transgenic mice [5].