...arginylation can have wide-ranging effects on the molecular and cellular levels through a single protein target.
The arginylation of β-actin regulates the actin cytoskeleton and cell motility, report Kashina and colleagues in Science. The post-translational addition of an Arg residue to the N terminus of a protein is important for embryogenesis, cardiovascular development and angiogenesis. However, until now, the molecular effects of arginylation, which is catalysed by Arg–tRNA protein transferase-1 (ATE1), and the proteins that are arginylated in vivo were largely unknown.
Actin undergoes N-terminal processing in vivo in such a way that it could become a target for arginylation. By analysing the actin isoforms in whole-cell lysates, the authors showed that Arg can be added to residue Asp3 of β-actin. They also estimated that ∼40% of β-actin is arginylated in vivo.
So what effect does this modification have? Arginylation has been proposed to mark proteins for degradation, but the authors found that β-actin stability was unaffected by this modification. Furthermore, by comparing immunoprecipitations from wild-type and ATE1−/− cells, they found that the interactions of β-actin with other proteins were unaffected by arginylation. However, they showed that arginylation affected the capability of actin to polymerize; in ATE1−/−-cell extracts, actin filaments clustered and formed filamentous aggregates.
Next, the authors analysed how arginylation affects the intracellular functions of β-actin by comparing the morphology, motility and actin cytoskeleton of wild-type and ATE1−/− cells. In the absence of arginylation, the intracellular β-actin distribution was altered and lamella formation was disrupted, which reduced the motility of ATE1−/− cells. These lamella defects could be rescued by transiently transfecting ATE1−/− cells with a 'permanently arginylated' β-actin construct.
Kashina and co-workers have therefore shown that arginylation can have wide-ranging effects on the molecular and cellular levels through a single protein target. They propose that the arginylation of β-actin adds bulky positive charges to actin filaments to prevent them from aggregating. This would facilitate the assembly of a loose actin network at the leading edge and regulate lamella formation in motile cells.
ORIGINAL RESEARCH PAPER
Karakozova, M. et al. Arginylation of beta actin regulates actin cytoskeleton and cell motility. Science 22 June 2006 (doi:10.1126/science.1129344)
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Smallridge, R. A modifier of motility. Nat Rev Mol Cell Biol 7, 552 (2006). https://doi.org/10.1038/nrm1991
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DOI: https://doi.org/10.1038/nrm1991