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A natural variant of the cysteine protease virulence factor of group A Streptococcus with an arginine-glycine-aspartic acid (RGD) motif preferentially binds human integrins alphavbeta3 and alphaIIbbeta3. Proc Natl Acad Sci U S A 1999 Jan 05;96(1):242-7 PMID: 9874803 PMCID: PMC15124

Pubmed ID

9874803

Abstract

The human pathogenic bacterium group A Streptococcus produces an extracellular cysteine protease [streptococcal pyrogenic exotoxin B (SpeB)] that is a critical virulence factor for invasive disease episodes. Sequence analysis of the speB gene from 200 group A Streptococcus isolates collected worldwide identified three main mature SpeB (mSpeB) variants. One of these variants (mSpeB2) contains an Arg-Gly-Asp (RGD) sequence, a tripeptide motif that is commonly recognized by integrin receptors. mSpeB2 is made by all isolates of the unusually virulent serotype M1 and several other geographically widespread clones that frequently cause invasive infections. Only the mSpeB2 variant bound to transfected cells expressing integrin alphavbeta3 (also known as the vitronectin receptor) or alphaIIbbeta3 (platelet glycoprotein IIb-IIIa), and binding was blocked by a mAb that recognizes the streptococcal protease RGD motif region. In addition, mSpeB2 bound purified platelet integrin alphaIIbbeta3. Defined beta3 mutants that are altered for fibrinogen binding were defective for SpeB binding. Synthetic peptides with the mSpeB2 RGD motif, but not the RSD sequence present in other mSpeB variants, blocked binding of mSpeB2 to transfected cells expressing alphavbeta3 and caused detachment of cultured human umbilical vein endothelial cells. The results (i) identify a Gram-positive virulence factor that directly binds integrins, (ii) identify naturally occurring variants of a documented Gram-positive virulence factor with biomedically relevant differences in their interactions with host cells, and (iii) add to the theme that subtle natural variation in microbial virulence factor structure alters the character of host-pathogen interactions.

Author List

Stockbauer KE, Magoun L, Liu M, Burns EH Jr, Gubba S, Renish S, Pan X, Bodary SC, Baker E, Coburn J, Leong JM, Musser JM

Author

Jenifer Coburn PhD Professor in the Medicine department at Medical College of Wisconsin




Scopus

2-s2.0-0033524449   84 Citations

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Bacterial Proteins
CHO Cells
Cell Adhesion
Cricetinae
Cysteine Endopeptidases
Endothelium, Vascular
Genetic Variation
Humans
Integrins
Oligopeptides
Peptide Fragments
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Binding
Receptors, Vitronectin
Recombinant Proteins
Streptococcus pyogenes
jenkins-FCD Prod-300 626508253d14e4184314fb9f66322a03a5906796