Diesterbeck Ulrike S, Muslinkina Liya A, Gittis Apostolos G, Singh Kavita, Moss Bernard, Garboczi David N
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Current address: Ceva Innovation Center GmbH, Am Pharmapark, 06861 Dessau-Rosslau, Germany.
bioRxiv. 2025 Jan 8:2025.01.08.631918. doi: 10.1101/2025.01.08.631918.
Poxviruses are exceptional in having an entry-fusion complex (EFC) consisting of eleven conserved proteins embedded in the membrane of mature virions. With the goal of understanding the function of the EFC, extensive efforts have been made to determine the structures and roles of its components, and to date, structures have been determined for nine of the eleven proteins. Here, we report the crystal structure of A21, the 10 EFC protein, comprising two α-helices clasping a twisted antiparallel β-sheet stabilized by two conserved disulfide bonds. The stability of each of the three A21 loops is provided by hydrogen bonds between main-chain atoms and several highly conserved residues, making the overall fold of A21 and its orthologs resilient to evolutionary change. Based on AlphaFold modeling and phylogenetic analysis of A21, we suggest that its highly conserved N-terminal transmembrane domain and C-terminal α-helix enable A21 integration into EFC, where it primarily interacts with the G3/L5 subcomplex and the smallest of EFC components, the O3 protein.
痘病毒的独特之处在于其具有一个由嵌入成熟病毒粒子膜中的11种保守蛋白组成的进入融合复合体（EFC）。为了了解EFC的功能，人们付出了巨大努力来确定其组成部分的结构和作用，到目前为止，已经确定了11种蛋白中9种的结构。在此，我们报告了EFC第10号蛋白A21的晶体结构，它由两个α螺旋环绕着一个扭曲的反平行β折叠片层组成，该结构由两个保守的二硫键稳定。A21的三个环中每个环的稳定性由主链原子与几个高度保守残基之间的氢键提供，这使得A21及其直系同源物的整体折叠结构对进化变化具有抗性。基于A21的AlphaFold建模和系统发育分析，我们认为其高度保守的N端跨膜结构域和C端α螺旋使A21能够整合到EFC中，在那里它主要与G3/L5亚复合体以及EFC最小的组成部分O3蛋白相互作用。
