4.8 Article

Oligomeric interactions maintain active-site structure in a noncooperative enzyme family

Journal

EMBO JOURNAL
Volume 41, Issue 17, Pages -

Publisher

WILEY
DOI: 10.15252/embj.2021108368

Keywords

cryo-EM; enzyme mechanism; oligomeric interactions; protein evolution; short-chain dehydrogenases-reductases

Funding

  1. National Key Research and Development Program of China [2018YFA0900300]
  2. National Science Foundation of China [31970045]
  3. National First-class Discipline Program of Light Industry Technology and Engineering [LITE2018-12]
  4. Research and Innovation Program for Graduate Students of Jiangsu Province, China [KYLX15-1148]
  5. High-end Foreign Experts Recruitment Program [G20190010083]
  6. NIH-NIGMS [5R01GM127883]
  7. China Scholarship Council

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The evolutionary benefit of oligomeric structures in proteins lacking evidence of intersubunit cooperativity is unclear. In this study, a conserved tetramer interface is shown to maintain the active-site structure in a certain class of proteins, the SDR superfamily. Oligomerization reduces the metabolic cost of enzyme biosynthesis and increases tolerance to destabilizing mutations, enhancing evolutionary fitness.
The evolutionary benefit accounting for widespread conservation of oligomeric structures in proteins lacking evidence of intersubunit cooperativity remains unclear. Here, crystal and cryo-EM structures, and enzymological data, demonstrate that a conserved tetramer interface maintains the active-site structure in one such class of proteins, the short-chain dehydrogenase/reductase (SDR) superfamily. Phylogenetic comparisons support a significantly longer polypeptide being required to maintain an equivalent active-site structure in the context of a single subunit. Oligomerization therefore enhances evolutionary fitness by reducing the metabolic cost of enzyme biosynthesis. The large surface area of the structure-stabilizing oligomeric interface yields a synergistic gain in fitness by increasing tolerance to activity-enhancing yet destabilizing mutations. We demonstrate that two paralogous SDR superfamily enzymes with different specificities can form mixed heterotetramers that combine their individual enzymological properties. This suggests that oligomerization can also diversify the functions generated by a given metabolic investment, enhancing the fitness advantage provided by this architectural strategy.

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