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Evolution avoids a pathological stabilizing interaction in the immune protein S100A9.

Joseph L Harman1,2, Patrick N Reardon3, Shawn M Costello4

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A specific mutation in S100A9 protein increases stability but blocks function by forming a pathological interaction. This interaction is evolutionarily avoided, revealing constraints on stabilizing mutations in protein evolution.

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Area of Science:

  • Biochemistry
  • Evolutionary Biology
  • Structural Biology

Background:

  • Protein stability is crucial for function, yet constraints on stabilizing mutations are less understood than destabilizing ones.
  • The innate immune protein S100A9 plays a role in Toll-like receptor 4 activation.
  • Understanding stabilizing mutation constraints can illuminate evolutionary pathways.

Purpose of the Study:

  • To investigate the evolutionary constraints on stabilizing mutations in the S100A9 protein.
  • To elucidate the molecular mechanism by which a stabilizing mutation impacts S100A9 function.
  • To explore how protein evolution avoids potentially deleterious stabilizing interactions.

Main Methods:

  • Site-directed mutagenesis to introduce the M63F mutation into human S100A9.
  • Chemical denaturation and Hydrogen-deuterium exchange (HDX) to assess protein stability.
  • Nuclear Magnetic Resonance (NMR) spectroscopy to determine the structure of the mutant protein.
  • Bioinformatic analysis of S100A9 sequences across different organisms.

Main Results:

  • The M63F mutation in S100A9 increased protein stability by favoring a calcium-bound conformation.
  • Structural analysis revealed the M63F mutation distorts the hydrophobic binding surface, disrupting Toll-like receptor 4 activation.
  • A stabilizing interaction was identified between Phe63 and Phe37, forming a molecular staple that locks S100A9 in a nonfunctional state.
  • Mutating Phe37 to Leu abolished the stabilizing effect and restored S100A9 biological activity.
  • Bioinformatic analysis showed that dual phenylalanine residues at positions 37 and 63 are rare in S100A9 across species.

Conclusions:

  • Stabilizing mutations can inadvertently lock proteins into nonfunctional conformations, posing an evolutionary constraint.
  • The M63F mutation in S100A9 exemplifies how stabilizing interactions can be detrimental to protein function.
  • Evolutionary avoidance of specific residue combinations (e.g., Phe37 and Phe63 in S100A9) highlights mechanisms for preventing pathological stabilization.