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

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.

Authors:
 [1];  [1];  [1]
  1. Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 (United States)
Publication Date:
OSTI Identifier:
20979856
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 355; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2007.01.116; PII: S0006-291X(07)00159-3; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; COMPLEXES; CYSTEINE; KIDNEYS; MORPHOLOGY; MUTANTS; PROTEINS; TOXICITY; ZINC

Citation Formats

Pan, Yong, Garg, Abhimanyu, and Agarwal, Anil K. Mislocalization of prelamin A Tyr646Phe mutant to the nuclear pore complex in human embryonic kidney 293 cells. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.01.116.
Pan, Yong, Garg, Abhimanyu, & Agarwal, Anil K. Mislocalization of prelamin A Tyr646Phe mutant to the nuclear pore complex in human embryonic kidney 293 cells. United States. https://doi.org/10.1016/j.bbrc.2007.01.116
Pan, Yong, Garg, Abhimanyu, and Agarwal, Anil K. 2007. "Mislocalization of prelamin A Tyr646Phe mutant to the nuclear pore complex in human embryonic kidney 293 cells". United States. https://doi.org/10.1016/j.bbrc.2007.01.116.
@article{osti_20979856,
title = {Mislocalization of prelamin A Tyr646Phe mutant to the nuclear pore complex in human embryonic kidney 293 cells},
author = {Pan, Yong and Garg, Abhimanyu and Agarwal, Anil K},
abstractNote = {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.},
doi = {10.1016/j.bbrc.2007.01.116},
url = {https://www.osti.gov/biblio/20979856}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 355,
place = {United States},
year = {Fri Mar 30 00:00:00 EDT 2007},
month = {Fri Mar 30 00:00:00 EDT 2007}
}