Research ArticleBiochemistry

The bacterial Ras/Rap1 site-specific endopeptidase RRSP cleaves Ras through an atypical mechanism to disrupt Ras-ERK signaling

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Science Signaling  02 Oct 2018:
Vol. 11, Issue 550, eaat8335
DOI: 10.1126/scisignal.aat8335

How Vibrio disrupts RAS signaling

Many pathogenic bacteria target the small GTPase Ras because it is critical for signaling pathways that control host cell biology and innate defenses. Highly virulent strains of the opportunistic pathogen Vibrio vulnificus produce a toxin that includes the Ras/Rap1-specific endopeptidase (RRSP) effector domain, which cleaves Ras but has no homology to known proteases. Biancucci et al. solved the crystal structure of RRSP, which showed similarity to a family of hydrolytic enzymes, and identified the catalytic residues required for RRSP to cleave KRAS. Cleavage by RRSP did not release any fragments or bound nucleotides from KRAS but altered the structure of KRAS so that nucleotide exchange was inhibited and it could not bind to its downstream effector RAF. These findings provide insight into the mechanism of an unusual protease and may prove useful for developing new strategies for targeting cancer-associated activated RAS proteins.

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