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The a-Actinin Family (actinogelin)

Page updated 27/2/03

A family of actin filament crosslinking and bundling protein which are typically calcium sensitive in non-muscle cells and calcium insensitive in  muscle cells.   Many of the early reports on proteins which gelate or bundle actin filaments are now known to belong to the a-actinin family.  Their early discovery is probably due to the fact that they are found in large amounts in a variety of tissues and organisms. 
Taylor Lab  Amy McGough Lab      

a-actinin is composed of two identical anti-parallel peptides, with the actin binding domain close to the N terminus, followed by 4 spectrin-like repeats and terminating with two EF-hands (calcium binding motifs).  In calcium insensitive isoforms these EF-hands are not active.   It is thought that calcium sensitivity of actin binding arises from the proximity of the EF-hand at the tail of one molecule abutting on the actin binding head of its partner.

Figure 1.  The a-actinin dimer.  CH = Calponin homology domain. Spectrin repeats 1-4, EF = EF hands Ca2+ binding domains.

Other a-actinin binding proteins.
A host of proteins other than actin are known to bind a-actinin. Many of these interactions are structural, especially in muscle cells, others are involved in signalling cascades and others (such as the EPEC protein Tir) are involved in pathogenesis (Table 1).

Interacting Protein Function References
CLP-36 PDZ-LIM Zhou et al, 1999; Vallenius et al, 2000
CRP Cysteine-rich protein Pomies et al, 1999
Integrin b1 Adhesion proteins linking to cytoskeleton Pavalko et al, 1991, Otey et al, 1993
MEKK1 Mitogen activated kinase Christerson et al, 1999
Palladin Focal adhesion protein Parast & Otey, 2000
Syndecan-4 A transmembranous glycoprotein which is also an adhesion molecule that interacts with integrins. Greene et al, 2003
Tir A protein from pathogenic E.coli that binds a-actinin to form the adhesive plaque known as the pedestal (see bacteria & the cytoskeleton). Goosney et al, 2000
Titin A structural component of the sarcomere Atkinson et al, 2000
Vinculin Focal adhesion protein Belkin & Koteliansky, 1987; Wachsstock et al, 1987
Zyxin Focal adhesion protein Reinhard et al, 1999
Table 1 a-actinin binding proteins
Microfilament Cross-linking vs Bundling

At low concentration of a-actinin relative to actin, viscosity is increased as the filaments are linked in an isotropic gel where the filaments meet each other.  At higher concentration a-actinin bundles, draws together filaments into parallel and/or anti-parallel actin filaments.  The balance between cross-linking and bundling is determined by a number of factors, a-actinin binds to filament bundles in preference to single filaments (Gratzi et al,1992), as the local concentration of binding sites is greater, however once an isotropic gel is formed the gel becomes locked into this configuration.  If an isotrpoic gel is pulled for example with a needle, this breaks the gel and aligns the filaments in the direction of the applied force and this then tips the balance permitting bundling ().  The balance can also be tipped by the severing action of the ADF/cofilins (Maciver et al, 1991).  Severing is thought to allow the short a-actinin decorated filaments to zip together.  Once zipping the filaments are now longer able to be severed by the ADF/cofilins (as severing by this group is passive - see severing by ADF/cofilins), thus large filament aggregates are formed in vitro (Maciver et al, 1991) and possibly in vivo (Aizawa et al, 1997).


Regulation by polyphosphoinositide

Many actin-binding proteins are regulated by polyphosphoinositides, particularly phosphatidylinositol 4,5 bis-phosphate (PIP2).  a-actinin from chicken smooth and skeletal muscle binds PIP2 through residues 168-184 a region within CH2 (Fukami et al, 1992; Fukami et al, 1994), the second calponin homology domain segment in the a-actinin family that strengthens the actin interaction but does not itself bind actin (Norwood et al, 2000). Whereas some (Fukami et al, 1992) find that PIP2 increased F-actin gelating activity of a-actinin, others (Fraley et al, 2003) find that PIP2 inhibit bundling of actin by a-actinin.  These differences probably reflect differences in the methods used.


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