Key Laboratory of Industrial Biotechnology of Ministry of Education and School of Biotechnology, Jiangnan University, Wuxi, China.
Department of Biological Sciences, 702 Sherman Fairchild Center, MC2434, Columbia University, New York, NY, USA.
EMBO J. 2022 Sep 1;41(17):e108368. doi: 10.15252/embj.2021108368. Epub 2022 Jul 8.
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.
在缺乏亚基协同作用证据的情况下，蛋白质中寡聚结构广泛保守的进化优势仍不清楚。在这里，晶体和 cryo-EM 结构以及酶学数据表明，在一类短链脱氢酶/还原酶（SDR）超家族的蛋白质中，保守的四聚体界面维持了活性位点结构。系统发育比较支持在单个亚基的情况下，需要更长的多肽来维持等效的活性位点结构。因此，寡聚化通过降低酶生物合成的代谢成本来提高进化适应性。结构稳定的寡聚界面的大表面积通过增加对增强活性但破坏稳定性的突变的耐受性，产生协同的适应性增益。我们证明，两种具有不同特异性的 SDR 超家族同工酶可以形成混合异四聚体，结合它们各自的酶学特性。这表明，寡聚化还可以使给定代谢投资产生的功能多样化，从而增强这种结构策略提供的适应性优势。
