Mislocalization of prelamin A Tyr646Phe mutant to the nuclear pore complex in human embryonic kidney 293 cells

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Mature lamin A is formed after post-translational processing of prelamin A, which includes prenylation and carboxymethylation of cysteine 661 in the CaaX motif, followed by two proteolytic cleavages by zinc metalloprotease (ZMPSTE24). We expressed several prelamin A mutants, C661S (defective in prenylation), Y646F (designed to undergo prenylation but not second proteolytic cleavage), double mutant, Y646F/C661S and Y646X (mature lamin A), and the wild-type construct in human embryonic kidney (HEK-293) cells. Only the Y646F mutant co-localized with nuclear pore complex proteins, including Nup53 and Nup98, whereas the other mutants localized to the nuclear envelope rim. The cells expressing Y646F mutant also revealed abnormal nuclear morphology which was partially rescued with the farnesyl transferase inhibitors. These data suggest that the unprenylated prelamin A is not toxic to the cells. The toxicity of prenylated prelamin A may be due to its association and/or accumulation at the nuclear pore complex which could be partially reversed by farnesyl transferase inhibitors.

Original languageEnglish (US)
Pages (from-to)78-84
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume355
Issue number1
DOIs
StatePublished - Mar 30 2007

    Fingerprint

Keywords

  • CaaX motif protein
  • Farnesyl transferase inhibitors
  • Lamin A/C
  • Lipodystrophy
  • Nuclear pore complex protein
  • Prenylation
  • Progeria
  • Zinc metalloprotease (ZMPSTE24)

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this