Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins

被引:4
作者
Song, Albert S. [1 ]
Poor, Taylor A. [1 ]
Abriata, Luciano A. [2 ,3 ]
Jardetzky, Theodore S. [4 ]
Dal Peraro, Matteo [2 ,3 ]
Lamb, Robert A. [1 ,5 ]
机构
[1] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA
[2] Ecole Polytech Fed Lausanne, Sch Life Sci, Inst Bioengn, CH-1050 Lausanne, Switzerland
[3] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland
[4] Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA
[5] Northwestern Univ, Howard Hughes Med Inst, Evanston, IL 60208 USA
基金
美国国家卫生研究院; 瑞士国家科学基金会;
关键词
molecular dynamics simulation; viral fusion protein; protein refolding; NEWCASTLE-DISEASE VIRUS; RESPIRATORY SYNCYTIAL VIRUS; HEMAGGLUTININ-NEURAMINIDASE; F-PROTEIN; MEMBRANE-FUSION; POSTFUSION CONFORMATION; NEUTRALIZING ANTIBODY; PROTEOLYTIC CLEAVAGE; MOLECULAR-DYNAMICS; 4-HELIX BUNDLE;
D O I
10.1073/pnas.1608349113
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Parainfluenza virus 5 (PIV5) is an enveloped, single-stranded, negative-sense RNA virus of the Paramyxoviridae family. PIV5 fusion and entry are mediated by the coordinated action of the receptor-binding protein, hemagglutinin-neuraminidase (HN), and the fusion protein (F). Upon triggering by HN, F undergoes an irreversible ATP-and pH-independent conformational change, going down an energy gradient from a metastable prefusion state to a highly stable postfusion state. Previous studies have highlighted key conformational changes in the F-protein refolding pathway, but a detailed understanding of prefusion F-protein metastability remains elusive. Here, using two previously described F-protein mutations (S443D or P22L), we examine the capacity tomodulate PIV5 F stability and the mechanisms by which these point mutants act. The S443D mutation destabilizes prefusion F proteins by disrupting a hydrogen bond network at the base of the F-protein globular head. The introduction of a P22L mutation robustly rescues destabilized F proteins through a local hydrophobic interaction between the N-terminal helix and a hydrophobic pocket. Prefusion stabilization conferred by a P22L-homologous mutation is demonstrated in the F protein of Newcastle disease virus, a paramyxovirus of a different genus, suggesting a conserved stabilizing structural element within the paramyxovirus family. Taken together, the available data suggest that movement of the N-terminal helix is a necessary early step for paramyxovirus F-protein refolding and presents a novel target for structure-based drug design.
引用
收藏
页码:E3844 / E3851
页数:8
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