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Mutant membrane protein toxicity

C Stewart1, J Bailey, C Manoil

  • 1Department of Genetics, University of Washington, Seattle, Washington, 98195, USA.

The Journal of Biological Chemistry
|October 17, 1998
PubMed
Summary
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Mutating the Escherichia coli lac permease (TM12) revealed critical transport residues and unexpected cellular toxicity. Many mutations, particularly frameshift and those disrupting membrane protein folding, severely reduced cell viability, suggesting a link to human degenerative diseases.

Area of Science:

  • Molecular Biology
  • Membrane Protein Function
  • Cellular Toxicology

Background:

  • Escherichia coli lac permease is a model for membrane transport proteins.
  • Integral membrane protein function is sensitive to mutations affecting structure and folding.

Purpose of the Study:

  • To investigate the functional and cellular consequences of mutations in the TM12 domain of E. coli lac permease.
  • To identify residues critical for lactose transport and assess the impact of mutations on protein stability and cell viability.

Main Methods:

  • Extensive mutational analysis of the TM12 sequence in E. coli lac permease.
  • Assessment of lactose transport activity and cell viability following mutagenesis.
  • Analysis of mutation types (frameshift, missense) and their correlation with toxicity.

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Main Results:

  • Identified specific residues essential for lactose transport function.
  • Demonstrated that numerous TM12 mutations induce significant cellular toxicity, reducing viability up to 10^4-fold.
  • Frameshift mutations and missense mutations disrupting membrane insertion/folding (e.g., introducing charged residues or prolines) were particularly toxic.

Conclusions:

  • Mutations altering integral membrane protein folding can commonly lead to cellular toxicity.
  • The observed toxicity mechanism may be analogous to the pathogenesis of human degenerative diseases involving mutant membrane proteins, such as retinitis pigmentosa, Charcot-Marie-Tooth, and Alzheimer's disease.