2024-03-28T15:43:09Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1339722023-01-04T11:01:16Zcom_10261_41com_10261_1col_10261_294
http://hdl.handle.net/10261/133972
10.1038/srep11969
313068
Structure and mechanism of a bacterial host-protein citrullinating virulence factor, Porphyromonas gingivalis peptidylarginine deiminase
Nature Publishing Group
2015
artículo
Goulas, Theodoros
García Ferrer, Irene
Guevara, Tibisay
rp11062
Millán, Claudia
rp11090
Usón, Isabel
rp11088
Solà, Maria
rp11085
Gomis-Rüth, F. Xavier
rp11048
2015-07-01
Theodoros Goulas et al.
Citrullination is a post-translational modification of higher organisms that deiminates arginines in proteins and peptides. It occurs in physiological processes but also pathologies such as multiple sclerosis, fibrosis, Alzheimer's disease and rheumatoid arthritis (RA). The reaction is catalyzed by peptidylarginine deiminases (PADs), which are found in vertebrates but not in lower organisms. RA has been epidemiologically associated with periodontal disease, whose main infective agent is Porphyromonas gingivalis. Uniquely among microbes, P. gingivalis secretes a PAD, termed PPAD (Porphyromonas peptidylarginine deiminase), which is genetically unrelated to eukaryotic PADs. Here, we studied function of PPAD and its substrate-free, substrate-complex, and substrate-mimic-complex structures. It comprises a flat cylindrical catalytic domain with five-fold α/β-propeller architecture and a C-terminal immunoglobulin-like domain. The PPAD active site is a funnel located on one of the cylinder bases. It accommodates arginines from peptide substrates after major rearrangement of a >Michaelis loop> that closes the cleft. The guanidinium and carboxylate groups of substrates are tightly bound, which explains activity of PPAD against arginines at C-termini but not within peptides. Catalysis is based on a cysteinehistidine-asparagine triad, which is shared with human PAD1-PAD4 and other guanidino-group modifying enzymes. We provide a working mechanism hypothesis based on 18 structure-derived point mutants.
Generalitat de Catalunya
Ministerio de Economía y Competitividad (España)
National Institutes of Health (US)
European Commission
Ministerio de Educación, Cultura y Deporte (España)
National Science Centre (Poland)
Scientific Reports
2015
5
11969