Actinin

There is belief that there is a common alpha-actinin like ancestor gene when looking at features in alpha-actinin and spectrin. Examining spectrin repeat sequences provides evidence for a two-stage model describing the evolution of the spectrin superfamily. In looking at their common ancestor, alpha-actinin and spectrin have four homologous repeats. Alpha-actinin-1 is necessary for the attachment of actin myofilaments to the Z-lines in skeletal muscle cells, and to the dense bodies in smooth muscle cells. Alpha-actinin 2 (ACTN2) is mainly found in cardiac and oxidative muscle fibers. Some of ACTN2 is seen in the brain. Alpha-actinin 3 (ACTN3) is typically found in type II muscle fibers, commonly known as fast twitch muscle fibers. == Structure ==

It has a N-terminus which all members of the superfamily have. This is made up of two consecutive calponin homology (CH) where spectrin repeats comes right after it. This allows for the length and flexibility of the actin binding protein to be decided. The actin-filament cross-links involve alpha-actinin, which is a functional anti-parallel dimer. This is then followed by a C-terminal calmodulin (CaM)-like domain which contain two EF-hand calcium binding motifs. This forms the binding site at each end of the protein which results in a rod-shaped molecule and with bundles of actin filaments. The rod shaped appearance is due to the SR region having a cylindrical shape. At each end there is the functional domain (ABD and CaM). The binding of calcium is only present in ACTN1 and ACTN4, while ACTN2 and ACTN3 have lost the ability to bind calcium. == Actin binding domain ==

Alpha-actinin and actin are both highly conserved proteins with alpha-actinin being the most conserved in the entire domain in the protein family. This is due to the ABD which binds to type 1 and type 2 CH domains (CH1, and CH2). The CH1-CH2 domain has a hydrophilic stabilizing portion and a hydrophobic part. The core of each CH domain has four helices (A, C, E, and G). Helices C and G are parallel to each other and the N-terminal helix A and E surrounds them. In humans, the crystal structures of ABDs were determined of alpha-actinin 1,3, and 4. The ABD forms a closed conformation. NMR has shown that there are three major ABD. The three sites are the N-terminal of the A helix of CH1, the C-terminal of the G helix of CH1, and to the inter-domain linker bordered by the N-terminal segment of the CH2 domain. These have a high affinity to the actin filaments. However, they must work together to have the highest affinity as CH2 can not bind actin filaments. With this being said, the actin-binding domain is located in the N-terminal region of the alpha-actinin molecule. == Metabolism ==

Alpha-actinin 3 (ACTN3) is deficient in around sixteen percent of humans and it plays a significant role in muscle metabolism. This deficiency is due to a premature stop codon polymorphism (R577X). The R577X gene was higher in endurance athletes than in sprint athletes. Among the four mammalian alpha-actinins, ACTN3 stands out as the most highly specialized, primarily expressed in fast glycolytic fibers within skeletal muscle. In humans that have ACTN3, scientists have seen better results in sprinting and power performance in athletes and the general population. Even though this has been found, recent positive selection appears to have influenced the null genotype XX, possibly owing to its emerging role in regulating muscle metabolism, as suggested by the available evidence. The lack of ACTN3 results in a more oxidative pathways of energy being used as glycogen phosphorylase activity is reduced. This lack of ACTN3 does not lead to clear cause for muscle disease but an alteration in muscle function has been seen. == Cancer ==

Alpha-actinin 4 (ACTN4) is expressed in non-muscle cells. It is important as it is the link between two tumor components. ACTN4 guides the connection between the actin cytoskeleton within the cell and the integrins that directly interact with the stromal ECM. Additionally, it can sense and respond to externally applied force. This process is crucial for the formation and continuation of breast, colorectal, ovarian, and pancreatic cancer. The explanation as to why ACTN4 contributes to cancer formation is still unknown. In melanoma cancer cells, ACTN4 plays a role in cellular morphology. It changes the cell from a more mesenchymal type cell to an amoeboid type cell by reducing the focal adhesion site. == See also ==