A new autocatalytic activation mechanism for cysteine proteases revealed by Prevotella intermedia interpain A.
Prevotella intermedia is a major periodontopathogen contributing to human gingivitis and periodontitis. Such pathogens release proteases as virulence factors that cause deterrence of host defenses and tissue destruction. A new cysteine protease from the cysteine-histidine-dyad class, interpain A, was studied in its zymogenic and self-processed mature forms. The latter consists of a bivalved moiety made up by two subdomains. In the structure of a catalytic cysteine-to-alanine zymogen variant, the right subdomain interacts with an unusual prodomain, thus contributing to latency. Unlike the catalytic cysteine residue, already in its competent conformation in the zymogen, the catalytic histidine is swung out from its active conformation and trapped in a cage shaped by a backing helix, a zymogenic hairpin, and a latency flap in the zymogen. Dramatic rearrangement of up to 20A of these elements triggered by a tryptophan switch occurs during activation and accounts for a new activation mechanism for proteolytic enzymes. These findings can be extrapolated to related potentially pathogenic cysteine proteases such as Streprococcus pyogenes SpeB and Porphyromonas gingivalis periodontain.
Mallorquí-Fernández
Noemí
N
Departament de Biologia Estructural, Institut de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Cientificas, c/Jordi Girona 18-26, Barcelona, Spain.
Manandhar
Surya P
SP
Mallorquí-Fernández
Goretti
G
Usón
Isabel
I
Wawrzonek
Katarzyna
K
Kantyka
Tomasz
T
Solà
Maria
M
Thøgersen
Ida B
IB
Enghild
Jan J
JJ
Potempa
Jan
J
Gomis-Rüth
F Xavier
FX
D000595:Amino Acid Sequence; D001483:Base Sequence; D002384:Catalysis; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D018713:Prevotella intermedia / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
D017931:DNA Primers; D004269:DNA, Bacterial; D004792:Enzyme Precursors; D011994:Recombinant Proteins; D003546:Cysteine Endopeptidases