Influenza A H5N1 hemagglutinin cleavable signal sequence substitutions.

Eleven influenza A H5N1 hemagglutinin N-terminal cleavable signal sequences, coded by single nucleotide substitutions relative to reference A/Viet Nam/1203/2004, were identified by BLASTN search of GenBank and were characterized by molecular modeling. The signal sequences statistically segregated into two classes of states. Members of one class were uncharged and conformationally compact while members of the second class each carried a 2+ electric charge and were conformationally extended. Virtual signal sequences, not found on GenBank and based upon hypothetical transversions in the third codon, had molecular characteristics intermediate to those of the two classes of actual signal sequences. The high incidence of non-synonymous substitutions (63.6%), the high transition/transversion ratio (10/1) and the results of molecular modeling all suggest that the N-terminal cleavable signal sequence is mutationally evolving more rapidly than proteins which must assume specific conformational states in the mature influenza virion.