Rapala Jackson R, Siddiq Mohammad, Wittkopp Patricia J, O'Meara Matthew J, O'Meara Teresa R
Department of Microbiology and Immunology, University of Michigan Medical School; Ann Arbor MI 48019 USA.
Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan Medical School; Ann Arbor MI 48019 USA.
bioRxiv. 2025 May 15:2025.05.14.654010. doi: 10.1101/2025.05.14.654010.
A central tenet of biology is that protein structure mediates the sequence-function relationship. Recently, there has been excitement about the promise of advances in protein structure modeling to generate hypotheses about sequence-structure-function relationships based on successes with controlled benchmarks. Here, we leverage structural similarity to identify rapidly evolving proteasome assembly chaperones and characterize their function in the emerging fungal pathogen . Despite the large sequence divergence, we demonstrate conservation of structure and function across hundreds of millions of years of evolution, representing a case of rapid neutral evolution. Using the functional constraints on structure from these naturally evolved sequences, we prospectively designed chaperones and demonstrate that these artificial proteins can rescue complex biological processes in the context of the whole cell.
生物学的一个核心原则是蛋白质结构介导序列-功能关系。最近，人们对蛋白质结构建模的进展充满期待，希望基于在可控基准测试中的成功，生成关于序列-结构-功能关系的假设。在这里，我们利用结构相似性来识别快速进化的蛋白酶体组装伴侣，并表征它们在新兴真菌病原体中的功能。尽管序列差异很大，但我们证明了在数亿年的进化过程中结构和功能的保守性，这代表了一种快速中性进化的情况。利用这些自然进化序列对结构的功能限制，我们前瞻性地设计了伴侣，并证明这些人工蛋白质可以在全细胞环境中拯救复杂的生物学过程。
