Single Amino Acid Substitutions Dramatically Shift Equilibria of Physiologically Relevant Alternate Protein Assemblies

Abstract

Increasing numbers of proteins are being revealed to “shape shift” in physiologically relevant ways that do not dramatically alter secondary structure. As each has been discovered they have been called morpheeins, transformers, metamorphic polymorphs, and others. In each case the alternate assemblies have different functions ranging from “on vs. off” to “moonlighting”. These examples continue to surprise their discoverers because they defy the “one sequence, one structure, one function” paradigm in an unexpected way. These alternate assemblies are likely physiologically relevant as their interconversion is thermodynamically feasible and the equilibrium of alternate assemblies is responsive to biological signals (e.g. pH, ligands). Experience now teaches that single amino acid substitutions can also dramatically shift an equilibrium of alternate assemblies. In some cases this shift is reasonably hypothesized, or established, to contribute to diseases such as inborn errors of metabolism and cancer.We present examples culled both from our work and the literature of such shape‐shifting proteins whose equilibria respond to single amino acid substitutions. Prime examples come from diverse branches of life, including viral proteins, bacterial proteins, and human metabolic enzymes. The growing number of such examples suggests that alternate assemblies, which have been called the fifth level of protein structure, may be a common factor in protein structure‐function relationships. Experience teaches that this fifth level of structure, for a given protein, may be revealed by the unexpected biophysical behavior of single amino acid variants.Support or Funding InformationNIH R01 NS100081 (EKJ)NIH R01 AI118016 (EOS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.