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J Virol 2013 Jan;87(1):345-53

The compensatory G88R change is essential in restoring the normal functions of influenza A/WSN/33 virus matrix protein 1 with a disrupted nuclear localization signal.

Xie H, Lin Z, Mosier PD, Desai UR, Gao Y

Abstract

G88R emerged as a compensatory mutation in the matrix protein 1 (M1) of influenza A/WSN/33 when its nuclear localization signal (NLS) was disrupted by R101S and R105S substitutions. The resultant M1 triple mutant M(NLS-88R) regained replication efficiency in vitro while remained attenuated in vivo with the potential of being a live vaccine candidate. To understand why G88R was favored by the virus as a compensatory change for the NLS loss and resultant replication deficiency, three more M1 triple mutants with an alternative G88K, G88V or G88E change in addition to R101S and R105S substitutions in NLS were generated. Unlike the other M1 triple mutants, M(NLS-88R) replicated more efficiently in vitro and in vivo. The G88R compensatory mutation not only restored normal functions of M1 in the presence of a disrupted NLS, but also resulted in a strong association of M1 with viral ribonucleoprotein. Under transmission electron microscope, only the M1 layer of M(NLS-88R) virion exhibited discontinuous "fingerprint"-like pattern with average thickness close to that of wild type A/WSN/33. Computational modeling suggested that the compensatory G88R change could re-establish the integrity of the M1 layer through new salt bridges between adjacent M1 subunits when the original interactions were interrupted by simultaneous R101S and R105S replacements in NLS. Our results suggested that restoring the normal functions of M1 was crucial for efficient virus replication.


Category: Journal Article
PubMed ID: #23077315 DOI: 10.1128/JVI.02024-12
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2012-06-22 Entry Last Modified: 2013-02-26
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