title: An analysis of splicing, actin-binding properties, heterodimerization and molecular interactions of the non-muscle α-actinins.
abstract: The non-muscle α-actinin isoforms (actinin-1 and -4) are closely related dimeric actin filament cross-linking proteins. Despite high sequence similarity, unique properties have been ascribed to actinin-4 in particular. For example, actinin-4, but not actinin-1, is essential for normal glomerular function in the kidney, is overexpressed in several cancers and can translocate to the nucleus to regulate transcription. To understand the molecular basis for such isoform-specific functions we have, for the first time, comprehensively compared these proteins in terms of alternative splicing, actin-binding properties, heterodimer formation and molecular interactions. We find that the Ca2+-insensitive variant of actinin-4 is expressed only in the nervous system and thus cannot be regarded as a smooth muscle isoform, as is the case for the Ca2+-insensitive variant of actinin-1. The actin-binding properties of actinin-1 and -4 are similar and are unlikely to explain isoform-specific functions. Surprisingly, we reveal that actinin-1/-4 heterodimers, rather than homodimers, are the most abundant form of actinin in many cell lines. Finally, we use a proteomics approach to identify potential isoform-specific interactions. The results of the present study indicate that actinin-1 and -4 can readily form heterodimers composed of monomers that may have different properties and interacting proteins. This significantly alters our view of non-muscle actinin function.
authors.affiliation: Department of Biochemistry, University College Cork, Cork, Ireland.
authors.forename: Kate S
authors.initials: KS
authors.lastname: Foley
authors.forename: Paul W
authors.initials: PW
authors.lastname: Young
mesh_terms: D000185:Actinin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D025941:Protein Interaction Mapping / Q000379:methods; D055503:Protein Multimerization / Q000235:genetics
chemical_list: C526905:ACTN1 protein, human; C111453:ACTN4 protein, human; D008840:Microfilament Proteins; D000185:Actinin