Crystal structure, folding, and operator binding of the hyperstable Arc repressor mutant PL8

Biochemistry. 1995 Jan 31;34(4):1405-12. doi: 10.1021/bi00004a035.

Abstract

Arc repressor is a small, dimeric DNA-binding protein that belongs to the ribbon-helix-helix family of transcription factors. Replacing Pro8 at the N-terminal end of the beta-sheet with leucine increases the stability of the mutant protein by 2.5 kcal/mol of dimer. However, this enhanced stability is achieved at the expense of significantly reduced DNA binding affinity. The structure of the PL8 mutant dimer has been determined to 2.4-A resolution by X-ray crystallography. The overall structure of the mutant is very similar to wild type, but Leu8 makes an additional interstrand hydrogen bond at each end of the beta-sheet of the mutant, increasing the total number of beta-sheet hydrogen bonds from six to eight. Comparison of the refolding and unfolding kinetics of the PL8 mutant and wild-type Arc shows that the enhanced stability of the mutant is accounted for by a decrease in the rate of protein unfolding, suggesting that the mutation acts to stabilize the native state and that the beta-sheet forms after the rate-limiting step in folding. The reduced operator affinity of the PL8 dimer appears to arise because the mutant cannot make the new interstrand hydrogen bonds and simultaneously make the wild-type set of contacts with operator DNA.

Publication types

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

MeSH terms

  • Crystallography, X-Ray
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / ultrastructure
  • Guanidine
  • Guanidines / chemistry
  • Hot Temperature
  • Hydrogen Bonding
  • Operator Regions, Genetic*
  • Protein Denaturation
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Repressor Proteins / metabolism*
  • Repressor Proteins / ultrastructure
  • Structure-Activity Relationship
  • Thermodynamics
  • Viral Proteins / metabolism*
  • Viral Proteins / ultrastructure
  • Viral Regulatory and Accessory Proteins

Substances

  • DNA-Binding Proteins
  • Guanidines
  • Repressor Proteins
  • Viral Proteins
  • Viral Regulatory and Accessory Proteins
  • phage repressor proteins
  • Guanidine