| Listeria monocytogenes is a food-borne, intracellular bacterial pathogen that causes severe and often fatal infections such as meningitis and septicemias in immunocompromised individuals, fetuses and neonates. A 67 kD surface attached protein internalinB (InlB) promotes host cell invasion by Listeria. InlB induces phagocytosis in a variety of host cells by activating the receptor tyrosine kinase Met and causing host cytoskeleton rearrangements. The Met binding site is located in the N-terminal leucine rich repeat (LRR) region of InlB, but the LRR fragment is unable to cause Met activation unless it is artificially dimerized through a disulfide bond. In contrast, activation of Met proceeds through monomers of intact InIB, and at physiologically relevant concentrations requires coordinated action in cis of both the N-terminal LRR region and C-terminal GW domains of InlB. The GW domains are crucial for potentiating Met activation by InlB, with this effect depending on association between GW domains and host glycosaminoglycans, which bind to the positively charged patches on the surface of the GW domains. Glycosaminoglycans do not alter the monomeric state of InlB, and probably enhance Met activation through a receptor-mediated mode, as opposed to the ligand-mediated mode observed for the LRR fragment.; The GW domains of InlB also bind to a host protein gC1q-R and associate non-covalently to the bacterial surface. gC1q-R, although implicated in InlB-mediated invasion of host cells, is found to specifically antagonize rather than enhance Met activation by InlB, and interaction between InlB and gC1q-R is unnecessary for bacterial invasion. The bacterial surface binding site is positioned on the lower positively charged patch of the third GW domain of InlB. Association of InlB to the surface of Listeria probably functions in temporally coupling the proximity of Listeria to host cells with induction of host cytoskeleton rearrangement and memembrane ruffling, which facilitates bacterial entry. |
