Respiratory pathogens, such as Neisseria meningitidis, secrete site-specific 
proteases able to cleave human immunoglobulin A1 (IgA1), the first line of 
defense at mucosal membranes. Bacterial isolates show wide variability in IgA1 
protease activity, and those isolated from patients with clinical infection 
possess the highest levels of activity. A feature of this enzyme is the 
self-cleavage required for secretion of the mature extracellular form. Known 
cleavage targets contain a proline-rich consensus recognition sequence, 
Pro-Pro-Ser-Pro, residing in the variable linker region that connects the 
protease and translocator domains. Here, we report the sequence of the NMB IgA1 
protease and the unexpected self-cleavage and subsequent extracellular release 
of mature IgA1 protease from mutants lacking the previously defined consensus 
cleavage site. We investigated the possible link between enzyme secretion and 
variability in the linker sequence segment using site-directed mutagenesis and 
linker domain swapping to construct mutated and chimeric forms of the IgA1 
protease from N. meningitidis strain NMB. The observed change in secreted 
activity levels compared to the wild-type clone indicated that the precise amino 
acid sequence of the intervening region, between mature IgA1 protease and the 
beta-core translocator domain, influences the efficacy of autoproteolytic 
processing. The broader specificity uncovered for the NMB IgA1 protease suggests 
that it could cleave a far wider range of human proteins than previously 
appreciated.