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Infection and Immunity, June 2007, p. 2875-2885, Vol. 75, No. 6
0019-9567/07/$08.00+0     doi:10.1128/IAI.01671-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Relaxed Cleavage Specificity of an Immunoglobulin A1 Protease from Neisseria meningitidis{triangledown}

Srdjan Vitovski and Jon R. Sayers*

Section of Infection, Inflammation and Immunity, Henry Wellcome Laboratories for Medical Research, The University of Sheffield School of Medicine and Biomedical Science, Sheffield S10 2RX, United Kingdom

Received 18 October 2006/ Returned for modification 30 November 2006/ Accepted 28 February 2007

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 β-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.

* Corresponding author. Mailing address: Section of Infection, Inflammation and Immunity, Henry Wellcome Laboratories for Medical Research, The University of Sheffield School of Medicine and Biomedical Science, Sheffield S10 2RX, United Kingdom. Phone: 44 114 2712327. Fax: 44 114 2713892. E-mail: j.r.sayers{at}shef.ac.uk

{triangledown} Published ahead of print on 12 March 2007.

Editor: J. N. Weiser

Infection and Immunity, June 2007, p. 2875-2885, Vol. 75, No. 6
0019-9567/07/$08.00+0     doi:10.1128/IAI.01671-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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