Gingipains from Porphyromonas gingivalis – Complexdomain structures confer diverse functions

摘要

Gingipains, a group of arginine or lysine specific cysteine proteinases (also known as RgpA, RgpB and Kgp), have been recognized as major virulence factors in Porphyromonas gingivalis. This bacterium is one of a handful of pathogens that cause chronic periodontitis. Gingipains are involved in adherence to and colonization of epithelial cells, haemagglutination and haemolysis of erythrocytes, disruption and manipulation of the inflammatory response, and the degradation of host proteins and tissues. RgpA and Kgp are multi-domain proteins composed of catalytic domains and haemagglutinin/adhesin (HA) regions. The structure of the HA regions have previously been defined by a gingipain domain structure hypothesis which is a set of putative domain boundaries derived from the sequences of fragments of these proteins extracted from the cell surface. However, multiple sequence alignments and hidden Markov models predict an alternative domain architecture for the HA regions of gingipains. In this alternate model, two or three repeats of the so-called “cleaved adhesin” domains (and one other undefined domain in some strains) are the modules which constitute the substructure of the HA regions. Recombinant forms of these putative cleaved adhesin domains are indeed stable folded proteinmodules and recently determined crystal structures support the hypothesis of amodular organisation of the HA region. Based on the observed K2 and K3structures as well as multiple sequence alignments, it is proposed that all thecleaved adhesin domains in gingipains will share the same β-sandwich jelly rollfold. The new domain model of the structure for gingipains and thehaemagglutinin (HagA) proteins of P. gingivalis will guidefuture functional studies of these virulence factors.