@article{6d5bdbd9bba141d2b4cfb8f8ebfa524b,
title = "Site-specific processing of Ras and Rap1 Switch i by a MARTX toxin effector domain",
abstract = "Ras (Rat sarcoma) protein is a central regulator of cell growth and proliferation. Mutations in the RAS gene are known to occur in human cancers and have been shown to contribute to carcinogenesis. In this study, we show that the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin-effector domain DUF5Vv from Vibrio vulnificus to be a site-specific endopeptidase that cleaves within the Switch 1 region of Ras and Rap1. DUF5Vv processing of Ras, which occurs both biochemically and in mammalian cell culture, inactivates ERK1/2, thereby inhibiting cell proliferation. The ability to cleave Ras and Rap1 is shared by DUF5Vv homologues found in other bacteria. In addition, DUF5Vv can cleave all Ras isoforms and KRas with mutations commonly implicated in malignancies. Therefore, we speculate that this new family of Ras/Rap1-specific endopeptidases (RRSPs) has potential to inactivate both wild-type and mutant Ras proteins expressed in malignancies.",
author = "Irena Antic and Marco Biancucci and Yueming Zhu and Gius, {David R.} and Satchell, {Karla J.F.}",
note = "Funding Information: We thank Brett Geissler, Shivangi Agarwal and Shivani Agarwal for helpful discussion, training in techniques and for providing purified PA. Kevin Ziolo, Jazel Dolores and Madeline Giegold provided technical assistance. We acknowledge input from Wayne Anderson, Cammie Lesser and Athanasios Vassilopoulos. Seema Mattoo provided plasmids for purification of GST-fusion proteins. The High Throughput Analysis Laboratory of Northwestern University provided access to the yeast deletion library and the Genomics Core Facility at Northwestern University provided sequence confirmation for plasmids. Michael Berne of the Tufts University Core Facility performed the Edman degradation experiments. The University of Illinois at Chicago Mass Spectrometry, Metabolomics and Proteomics Facility performed tandem mass spectrometry. This work was supported by NIH grants R01AI051490, R01AI092825 and R01AI098369 (to K.J.F.S); by NIH grants R01CA152601, R01CA152799 and R01CA168292, and a Northwestern University Avon Center of Excellence grant (to D.R.G.); and by the Northwestern Medicine Catalyst Fund. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",
year = "2015",
month = jun,
day = "8",
doi = "10.1038/ncomms8396",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}