Site-2 protease substrate specificity and coupling in trans by a PDZ-substrate adapter protein Journal Article
| Authors: | Schneider, J. S.; Reddy, S. P.; Hock, Y. E.; Evans, H. W.; Glickman, M. S. |
| Article Title: | Site-2 protease substrate specificity and coupling in trans by a PDZ-substrate adapter protein |
| Abstract: | Site-2 proteases (S2Ps) are intramembrane metalloproteases that cleave transmembrane substrates in all domains of life. Many S2Ps, including human S2P and Mycobacterium tuberculosis Rip1, have multiple substrates in vivo, which are often transcriptional regulators. However, S2Ps will also cleave transmembrane sequences of nonsubstrate proteins, suggesting additional specificity determinants. Many S2Ps also contain a PDZ domain, the function of which is poorly understood. Here, we identify an M. tuberculosis protein, PDZ-interacting protease regulator 1 (Ppr1), which bridges between the Rip1 PDZ domain and anti-sigma factor M (Anti-SigM), a Rip1 substrate, but not Anti-SigK or Anti-SigL, also Rip1 substrates. In vivo analyses of Ppr1 function indicate that it prevents nonspecific activation of the Rip1 pathway while coupling Rip1 cleavage of Anti-SigM, but not Anti-SigL, to site-1 proteolysis. Our results support a model of S2P substrate specificity in which a substratespecific adapter protein tethers the S2P to its substrate while holding the protease inactive through its PDZ domain. |
| Keywords: | signal transduction; unclassified drug; nonhuman; protein function; protein localization; protein degradation; protein protein interaction; genetic transcription; bacterial virulence; alkaline phosphatase; mycobacterium tuberculosis; beta galactosidase; proteinase; protein structure; tuberculosis; mycobacterium smegmatis; intramembrane proteolysis; sigma factor; pdz protein; pdz domain; priority journal; article; anti sigma factor k; anti sigma factor l; anti sigma factor m; brinase; pdz interacting protease regulator 1; site 2 protease |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 110 |
| Issue: | 48 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2013-11-26 |
| Start Page: | 19543 |
| End Page: | 19548 |
| Language: | English |
| DOI: | 10.1073/pnas.1305934110 |
| PROVIDER: | scopus |
| PMCID: | PMC3845159 |
| PUBMED: | 24218594 |
| DOI/URL: | |
| Notes: | Export Date: 2 January 2014 -- CODEN: PNASA -- Source: Scopus |
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