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Amino acid substitution at the dimeric interface of human manganese superoxide dismutase

Academic Article
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Overview

authors

  • Hearn, A. S.
  • Fan, L.
  • Lepock, J. R.
  • Luba, J. P.
  • Greenleaf, W. B.
  • Cabelli, D. E.
  • Tainer, John
  • Nick, H. S.
  • Silverman, D. N.

publication date

  • February 2004

journal

  • Journal of Biological Chemistry  Journal

abstract

  • The side chains of His30 and Tyr166 from adjacent subunits in the homotetramer human manganese superoxide dismutase (Mn-SOD) form a hydrogen bond across the dimer interface and participate in a hydrogen-bonded network that extends to the active site. Compared with wild-type Mn-SOD, the site-specific mutants H30N, Y166F, and the corresponding double mutant showed 10-fold decreases in steady-state constants for catalysis measured by pulse radiolysis. The observation of no additional effect upon the second mutation is an example of cooperatively interacting residues. A similar effect was observed in the thermal stability of these enzymes; the double mutant did not reduce the major unfolding transition to an extent greater than either single mutant. The crystal structures of these site-specific mutants each have unique conformational changes, but each has lost the hydrogen bond across the dimer interface, which results in a decrease in catalysis. These same mutations caused an enhancement of the dissociation of the product-inhibited complex. That is, His30 and Tyr166 in wild-type Mn-SOD act to prolong the lifetime of the inhibited complex. This would have a selective advantage in blocking a cellular overproduction of toxic H2O2.

subject areas

  • Amino Acids
  • Binding Sites
  • Calorimetry, Differential Scanning
  • Catalysis
  • Crystallography, X-Ray
  • Dimerization
  • Escherichia coli
  • Histidine
  • Humans
  • Hydrogen Bonding
  • Hydrogen Peroxide
  • Kinetics
  • Models, Chemical
  • Models, Molecular
  • Mutation
  • Oxidation-Reduction
  • Protein Folding
  • Spectrophotometry
  • Superoxide Dismutase
  • Time Factors
  • X-Ray Diffraction
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M311310200

PubMed ID

  • 14638684
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Additional Document Info

start page

  • 5861

end page

  • 5866

volume

  • 279

issue

  • 7

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