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Ssy5 is a signaling serine protease that exhibits atypical biogenesis and marked S1 specificity
Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, SE-10691 Stockholm, Sweden..
Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, SE-10691 Stockholm, Sweden.;Martin Luther Univ Halle Wittenberg, Inst Physiol Chem, D-06114 Halle, Germany..
Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, SE-10691 Stockholm, Sweden.;Sanofi Aventis Deutschland GmbH, Global Business Dev & Licensing Consumer Healthca, D-65926 Frankfurt, Germany..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Glycoscience.
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 22, p. 8362-8378Article in journal (Refereed) Published
Abstract [en]

Ssy5 is a signaling endoprotease that plays a key role in regulating central metabolism, cellular aging, and morphological transitions important for growth and survival of yeast (Saccharomyces cerevisiae) cells. In response to extracellular amino acids, Ssy5 proteolytically activates the transcription factors Stp1 and Stp2, leading to enhanced Ssy1-Ptr3-Ssy5 (SPS) sensor-regulated gene expression. Ssy5 comprises a catalytic (Cat) domain and an extensive regulatory prodomain. Ssy5 is refractory to both broad-spectrum and serine protease-specific inhibitors, confounding its classification as a protease, and no information about Ssy5's cleavage-site preferences and its mechanism of substrate selection is available. Here, using mutational and inhibition experiments, we investigated the biogenesis and catalytic properties of Ssy5 and conclusively show that it is a serine protease. Atypical for the majority of serine proteases, Ssy5's prodomain was obligatorily required in cis during biogenesis for the maturation of the proteolytic activity of the Cat domain. Autolysis and Stp1 and Stp2 cleavage occurred between a cysteine (at the P1 site) and a serine or alanine (at the P1 site) and required residues with short side chains at the P1 site. Substitutions in the Cat domain affecting substrate specificity revealed that residues Phe-634, His-661, and Gly-671 in the S1-binding pocket of this domain are important for Ssy5 catalytic function. This study confirms that the signaling protease Ssy5 is a serine protease and provides a detailed understanding of the biogenesis and intrinsic properties of this key enzyme in yeast.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC , 2018. Vol. 293, no 22, p. 8362-8378
Keywords [en]
Saccharomyces cerevisiae, serine protease, signal transduction, substrate specificity, yeast, enzyme structure, environmental sensing, receptor activated proteolysis, signaling protease, SPS sensor, zymogen
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-230826DOI: 10.1074/jbc.RA118.002457ISI: 000434205700004PubMedID: 29661936Scopus ID: 2-s2.0-85048036415OAI: oai:DiVA.org:kth-230826DiVA, id: diva2:1220734
Note

QC 20180619

Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-25Bibliographically approved

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Bulone, Vincent

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