Group:MUZIC:actinin2: Difference between revisions

===α-actinin-2===

== Introduction ==

Muscle cells are responsible for the voluntary and involuntary contraction. These cells contains myofibrils, which are bundles mainly formed by actin and myosin filaments. These filaments are organized into repetitive subunits, called sarcomeres, which are connected in tandem by Z-disks, constituting an intricate macromolecular assembly. A plethora of proteins have been identified in the Z-disk [[http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome]], members of different protein classes - globular, intrinsically disordered and multi-domain proteins, but the details about their structure and interaction network at molecular level are still an enigma. Understanding how these proteins work together and how they interact with other molecules can have major impacts in medicine.

α-actinin-2 is a calcium-independent isoform expressed in all muscle fibers. The expression in human skeletal muscle overlaps α-actinin-3. Both proteins form heterodimers in vitro and in vivo and share high protein sequence identity (80%),  therefore suggesting a high 3-D structure similarity. They are regulated by phosphoinositides, rendering alpha-actinin capable of binding to titin (and some other Z-disk partners). It is worth pointing out that the other α-actinin non-muscles isoforms (1 and 4) are calcium-dependent. α-actinin-1 is associate with cell adhesion molecules, stabilizing cell adhesion and regulating cell shape and cell motility, while α-actinin-4 are related to the cytoskeleton playing an essential role in cell motility and shape and tumor suppressor activity.

At the ABD domain three actin binding sites (ABS) are mapped to be important for the interaction to F-actin. ABS 1 and 2 spanning the amino acids residues 48–57 and 123–147, which are located at the CH1 domain, while ABS 2 (residues 153–172) are found at the CH2 domain <ref name="ABD domain">PMID:15808860</ref>. The spectrin like repeats of α-actinin-2 are required for the binding to the C-terminal region of the FATZ [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin], and myotilin [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin], myopodin [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myopodin]. EF3-4 domains of α-actinin-2 binds Z-repeat 1 and 7 of titin simultaneously to PDZ domain of ZASP protein [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family] <ref>PMID: 10427098</ref> <ref>PMID: 15062084</ref>. For the complete list of α-actinin-2 Z-disc protein partners access the following link [[http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome]]

== Structures ==

The solution structure of the complex between the human α-actinin-2 EF-hand domain and the chicken titin Z-repeat 7 domain was solved by NMR spectroscopy. A specific set of contacts and some important residues for protein-protein interactions were identified. It was shown that recognition and positioning of Z-repeat in cavity of EF-hand domain is mediated by balance of electrostatic and hydrophobic interactions. The reported semi-open conformation of complex is commonly seen in homologous structures. This conformation seems to be typical for calcium-independent recognition by EF-hand domain and is fully compatible with formation of stable long-term complexes between titin and α-actinin-2.

==Pathology==

Hypertrophic cardiomyopathy (HCM) is a genetically transmitted disease and an important cause of morbidity and sudden cardiac death in young people, including competitive athletes <ref>PMID: 7641357</ref>. Recently, Chiu et al (2010) <ref>PMID: 20022194</ref> have reported a list of point mutation in the ''ACTN2'' gene related to hypertrophic cardiomyopathy (Gln9Arg, Gly111Val, Ala119Thr, Thr495Met, Glu583Ala, Glu628Gly, Arg759Thr). However, the impact of these mutation in the α-actinin-2 protein structure and function is poorly understood.

==References==

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