The crystal structure of the K1 domain, an adhesin module of the lysine gingipain (Kgp) expressed on the cell surface by the periodontopathic anaerobic bacterium, Porphyromonas gingivalis W83, is compared to the previously determined structures of homologues K2 and K3, all three being representative members of the cleaved adhesin domain family. In the structure of K1, the conformation of the most extensive surface loop is unexpectedly perturbed, perhaps by crystal packing, and is displaced from a previously reported arginine-anchored position observed in K2 and K3. This displacement allows the loop to become free to interact with other proteins; the alternate flipped-out loop conformation is a novel mechanism for interacting with target host proteins, other bacteria, or other gingipain protein domains. Further, the K1 adhesin module, like others, is found to be haemolytic in vitro, and so, functions in erythrocyte recognition thereby contributing to the haemolytic function of Kgp. K1 was also observed to selectively bind to haem-albumin with high affinity, suggesting this domain may be involved in gingipain-mediated haem acquisition from haem-albumin. Therefore, it is most likely that all cleaved adhesin domains of Kgp contribute to the pathogenicity of P. gingivalis in more complex ways than simply mediating bacterial adherence. Keywords: Porphyromonas gingivalis, gingipain adhesins, virulence factor, protein structure, oral infection IntroductionChronic periodontitis is an infl ammatory disorder of the supporting structures of the teeth in response to the buildup of dental plaque, which is most commonly a result of poor oral hygiene. Progression to this advanced form of periodontal disease from the preventable gingivitis gives rise to the destruction of the periodontium and subsequent loss of teeth [1][2][3]. This disease is the primary cause of tooth loss in the human population [4], and there is a growing concern that it may be associated with other chronic disorders such as cardiovascular diseases [5], diabetes mellitus [6,7], rheumatoid arthritis [8], and some forms of cancer [9]. This suggests that severe periodontal disease not only affects the oral cavity but may infl uence the overall wellbeing of an individual.Selected microorganisms have been implicated in the pathogenesis of periodontal disease, but it is the Gram-negative anaerobic bacterium, Porphyromonas gingivalis, that is most strongly associated with disease severity [1,10,11]. P. gingivalis expresses a large array of proteolytic enzymes that bind, lyse, and degrade erythrocytes to release haemoglobin, providing a source of peptides, iron, and haem for this asaccharolytic porphyrin-auxotroph [2,[12][13][14][15]. Because of this, P. gingivalis is often abundant in bleeding chronic periodontal lesions that provide haemoglobin released from ruptured erythrocytes [1].P. gingivalis can either passively survive within oral epithelial cells or it can aggressively disrupt the host immune response through a number of mechanisms, of which a group of cys...

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