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Programmed ribosomal frameshifting in the human gene PLEKHM2 allows for a second protein to be made. This frameshifted protein is essential for normal cardiomyocyte function.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Programmed ribosomal frameshifting is a known mechanism, primarily in viruses, for generating protein diversity.
  • Conserved frameshifting events in nuclear-encoded human genes are rare.
  • The human gene PLEKHM2's function and regulation were not fully understood.

Purpose of the Study:

  • To investigate a novel programmed ribosomal frameshifting event in the human gene PLEKHM2.
  • To characterize the function of the protein produced by this frameshifting event.
  • To determine the role of PLEKHM2 frameshifting in cardiac cell function.

Main Methods:

  • Analysis of mRNA and protein products from the human PLEKHM2 gene.
  • Site-directed mutagenesis to study frameshifting efficiency.
  • Creation and analysis of PLEKHM2 knockout cardiomyocyte models.
  • Reintroduction of both canonical and frameshifted PLEKHM2 proteins.

Main Results:

  • A +1 programmed ribosomal frameshifting event was identified in the human PLEKHM2 gene, yielding an internally overlapping open reading frame (ORF).
  • The frameshifted PLEKHM2 protein possesses a novel alpha-helical carboxyl-terminal domain that alleviates autoinhibition.
  • This frameshift protein enables cellular localization to cell tips independently of ARL8 activation.
  • Restoration of normal cardiomyocyte contractile function requires both the canonical and frameshifted PLEKHM2 proteins.

Conclusions:

  • Programmed ribosomal frameshifting in PLEKHM2 is crucial for generating a functional protein variant.
  • The frameshifted PLEKHM2 protein plays a vital role in regulating cardiomyocyte contractility.
  • This discovery highlights the significance of frameshifting in nuclear-encoded genes for cellular processes.