There is increasing evidence for strong genetic influences on athletic performance and for an evolutionary “trade-off” between performance traits for speed and endurance activities. We have recently demonstrated that the skeletal-muscle actin-binding protein α-actinin-3 is absent in 18% of healthy white individuals because of homozygosity for a common stop-codon polymorphism in the ACTN3 gene, R577X. α-Actinin-3 is specifically expressed in fast-twitch myofibers responsible for generating force at high velocity. The absence of a disease phenotype secondary to α-actinin-3 deficiency is likely due to compensation by the homologous protein, α-actinin-2. However, the high degree of evolutionary conservation of ACTN3 suggests function(s) independent of ACTN2. Here, we demonstrate highly significant associations between ACTN3 genotype and athletic performance. Both male and female elite sprint athletes have significantly higher frequencies of the 577R allele than do controls. This suggests that the presence of α-actinin-3 has a beneficial effect on the function of skeletal muscle in generating forceful contractions at high velocity, and provides an evolutionary advantage because of increased sprint performance. There is also a genotype effect in female sprint and endurance athletes, with higher than expected numbers of 577RX heterozygotes among sprint athletes and lower than expected numbers among endurance athletes. The lack of a similar effect in males suggests that the ACTN3 genotype affects athletic performance differently in males and females. The differential effects in sprint and endurance athletes suggests that the R577X polymorphism may have been maintained in the human population by balancing natural selection.

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ACTN3 Genotype Is Associated with Human Elite Athletic Performance

Cadherins are Ca(2+)-dependent, cell surface glycoproteins involved in cell-cell adhesion. Extracellularly, transmembrane cadherins such as E-, P-, and N-cadherin self-associate, while intracellularly they interact indirectly with the actin-based cytoskeleton. Several intracellular proteins termed catenins, including alpha-catenin, beta-catenin, and plakoglobin, are tightly associated with these cadherins and serve to link them to the cytoskeleton. Here, we present evidence that in fibroblasts alpha-actinin, but not vinculin, colocalizes extensively with the N-cadherin/catenin complex. This is in contrast to epithelial cells where both cytoskeletal proteins colocalize extensively with E-cadherin and catenins. We further show that alpha-actinin, but not vinculin, coimmunoprecipitates specifically with alpha- and beta-catenin from N- and E-cadherin-expressing cells, but only if alpha-catenin is present. Moreover, we show that alpha-actinin coimmunoprecipitates with the N-cadherin/catenin complex in an actin-independent manner. We therefore propose that cadherin/catenin complexes are linked to the actin cytoskeleton via a direct association between alpha-actinin and alpha-catenin.

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Interaction of alpha-actinin with the cadherin/catenin cell-cell adhesion complex via alpha-catenin.

▪ Abstract Striated muscle is an intricate, efficient, and precise machine that contains complex interconnected cytoskeletal networks critical for its contractile activity. The individual units of the sarcomere, the basic contractile unit of myofibrils, include the thin, thick, titin, and nebulin filaments. These filament systems have been investigated intensely for some time, but the details of their functions, as well as how they are connected to other cytoskeletal elements, are just beginning to be elucidated. These investigations have advanced significantly in recent years through the identification of novel sarcomeric and sarcomeric-associated proteins and their subsequent functional analyses in model systems. Mutations in these cytoskeletal components account for a large percentage of human myopathies, and thus insight into the normal functions of these proteins has provided a much needed mechanistic understanding of these disorders. In this review, we highlight the components of striated muscle cyt...

Striated muscle cytoarchitecture: an intricate web of form and function.

The mechanisms by which neurotransmitter receptors are immobilized at postsynaptic sites in neurons are largely unknown. The activity of NMDA (N-methyl-D-aspartate) receptors is mechanosensitive1 and dependent on the integrity of actin2, suggesting a functionally important interaction between NMDA receptors and the postsynaptic cytoskeleton. α-Actinin-2, a member of the spectrin/dystrophin family of actin-binding proteins, is identified here as a brain postsynaptic density protein that colocalizes in dendritic spines with NMDA receptors and the putative NMDA receptor-clustering molecule PSD-95. α-Actinin-2 binds by its central rod domain to the cytoplasmic tail of both NR1 and NR2B subunits of the NMDA receptor, and can be immunoprecipitated with NMDA receptors and PSD-95 from rat brain. Intriguingly, NR1-α-actinin binding is directly antagonized by Ca2+/calmodulin. Thus α-actinin may play a role in both the localization of NMDA receptors and their modulation by Ca2+.

Competitive binding of α-actinin and calmodulin to the NMDA receptor

This article outlines the present knowledge of the architecture, molecular composition, and dynamics of focal contacts of adhesive animal cells. These structures, developed at the plasma membrane at sites where cells touch their substratum, are essential for cellular attachment in tissue formation during embryogenesis and wound healing. In tissue culture, they are particularly prominent and thus amenable to detailed investigation. Focal contacts consist of a cytoplasmic face, comprising cytoskeletal elements, a transmembrane connecting region, and a extracellular face composed of proteins of the extracellular matrix. The molecular anatomy of the numerous proteins involved, the basis for classifying them as structural or regulatory components, and their in vitro interactions are described. Based on this information, current models on the dynamics of their assembly and of possible regulatory mechanisms involving a variety of signal transduction pathways are discussed.

Andrew D. Blanchard

Papers

The structure and function of α-actinin

Mutually exclusive splicing of calcium-binding domain exons in chick alpha-actinin.

The cDNA sequence of a human placental α-actinin