A concerted mechanism for the suppression of a folding defect through interactions with chaperones

J Biol Chem. 2004 Apr 23;279(17):17473-82. doi: 10.1074/jbc.M400467200. Epub 2004 Feb 4.

Abstract

Specific amino acid substitutions confer a temperature-sensitive-folding (tsf) phenotype to bacteriophage P22 coat protein. Additional amino acid substitutions, called suppressor substitutions (su), relieve the tsf phenotype. These su substitutions are proposed to increase the efficiency of procapsid assembly, favoring correct folding over improper aggregation. Our recent studies indicate that the molecular chaperones GroEL/ES are more effectively recruited in vivo for the folding of tsf:su coat proteins than their tsf parents. Here, the tsf:su coat proteins are studied with in vitro equilibrium and kinetic techniques to establish a molecular basis for suppression. The tsf:su coat proteins were monomeric, as determined by velocity sedimentation analytical ultracentrifugation. The stability of the tsf:su coat proteins was ascertained by equilibrium urea titrations, which were best described by a three-state folding model, N <--> I <--> U. The tsf:su coat proteins either had stabilized native or intermediate states as compared with their tsf coat protein parents. The kinetics of the I <--> U transition showed a decrease in the rate of unfolding and a small increase in the rate of refolding, thereby increasing the population of the intermediate state. The increased intermediate population may be the reason the tsf:su coat proteins are aggregation-prone and likely enhances GroEL-ES interactions. The N --> I unfolding rate was slower for the tsf:su proteins than their tsf coat parents, resulting in an increase in the native state population, which may allow more competent interactions with scaffolding protein, an assembly chaperone. Thus, the suppressor substitution likely improves folding in vivo through increased efficiency of coat protein-chaperone interactions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Bacteriophage P22 / metabolism*
  • Capsid Proteins / chemistry*
  • Chaperonin 10 / chemistry
  • Chaperonin 60 / chemistry
  • Circular Dichroism
  • Dose-Response Relationship, Drug
  • Kinetics
  • Models, Chemical
  • Phenotype
  • Protein Binding
  • Protein Folding
  • Protein Structure, Tertiary
  • Spectrometry, Fluorescence
  • Temperature
  • Thermodynamics
  • Ultracentrifugation
  • Urea / pharmacology

Substances

  • Capsid Proteins
  • Chaperonin 10
  • Chaperonin 60
  • Urea