The actinin family of actin cross-linking proteins - a genetic perspective

Abstract

Actinins are one of the major actin cross-linking proteins found in virtually all cell types and are the ancestral proteins of a larger family that includes spectrin, dystrophin and utrophin. Invertebrates have a single actinin-encoding ACTN gene, while mammals have four. Mutations in all four human genes have now been linked to heritable diseases or traits. ACTN1 mutations cause macrothrombocytopenia, a platelet disorder characterized by excessive bleeding. ACTN2 mutations have been linked to a range of cardiomyopathies, and ACTN4 mutations cause a kidney condition called focal segmental glomerulosclerosis. Intriguingly, approximately 16 % of people worldwide are homozygous for a nonsense mutation in ACTN3 that abolishes actinin-3 protein expression. This ACTN3 null allele has undergone recent positive selection in specific human populations, which may be linked to improved endurance and adaptation to colder climates. In this review we discuss the human genetics of the ACTN gene family, as well as ACTN gene knockout studies in several model organisms. Observations from both of these areas provide insights into the evolution and cellular functions of actinins.

Keywords: ACTN1; ACTN2; ACTN3; ACTN4; Actin binding proteins; Actin cross-linking; Actinin; Alpha-actinin.

Fig. 1

Schematic representation of the actinin dimer. The domain organization of the anti-parallel actinin dimer is depicted schematically in the closed conformation as observed in the X-ray crystallographic structure of the human actinin-2 [4]. In each subunit two calponin homology (CH) domains make up the N-terminal actin-binding domain (ABD). The rod domain composed of four spectrin-like repeats (SLR1-4) makes up the bulk of the dimer interface. The carboxyl terminal calmodulin-like (CaM) domain is made up of two pairs of EF-hand motifs (EF1/2 and EF3/4). EF1/2 binds Ca⁺⁺ in some actinins [1]. EF3/4 from one subunit interacts with the “neck” region between the ABD and first SLR of the opposing monomer (depicted as a line) [3]. This interaction clamps the protein into a closed conformation that is thought to be opened up by phospholipid binding to the ABD [4, 3]