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Here, we show that the periplasmic sensor domain of <jats:styled-content style=\"fixed-case\">SsrA<\/jats:styled-content> is enriched in histidine residues that increase <jats:styled-content style=\"fixed-case\">SsrA<\/jats:styled-content> signaling below external pH of 6. While no single histidine accounted for the full acid\u2010responsiveness of <jats:styled-content style=\"fixed-case\">SsrA<\/jats:styled-content>, we localized the acid\u2010responsiveness principally to five histidines in the <jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>\u2010terminal end of the periplasmic sensor domain, with input from additional histidines in the <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>\u2010terminal end of the senor. A sensor mutant lacking critical pH\u2010responsive histidines was defective for acid\u2010promoted activity, yet retained basal activity similar to wild type at neutral pH, indicating that the role of these histidines is to enhance signaling in response to acidification. In support of this, a pH\u2010blind mutant was insensitive to the vacuole acidification blocking activity of bafilomycin, and was attenuated for competitive fitness during infection of mice. Our data demonstrate that <jats:styled-content style=\"fixed-case\">SsrA<\/jats:styled-content> contains a histidine\u2010rich periplasmic sensor that enhances signaling in response to the innate host defense of vacuolar acidification.<\/jats:p>","DOI":"10.1111\/mmi.12895","type":"journal-article","created":{"date-parts":[[2014,12,2]],"date-time":"2014-12-02T07:11:25Z","timestamp":1417504285000},"page":"678-691","source":"Crossref","is-referenced-by-count":32,"title":["Multiple histidines in the periplasmic domain of the <scp><i>S<\/i><\/scp><i>almonella enterica<\/i> sensor kinase <scp>SsrA<\/scp> enhance signaling in response to extracellular acidification"],"prefix":"10.1111","volume":"95","author":[{"given":"David T.","family":"Mulder","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences McMaster University  Hamilton ON L8N\u20093Z5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph B.","family":"McPhee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences McMaster University  Hamilton ON L8N\u20093Z5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Reid\u2010Yu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences McMaster University  Hamilton ON L8N\u20093Z5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Stogios","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Applied Chemistry Banting and Best Department of Medical Research University of Toronto  Toronto Ontario M5G\u20091L6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexei","family":"Savchenko","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Applied Chemistry Banting and Best Department of Medical Research University of Toronto  Toronto Ontario M5G\u20091L6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian K.","family":"Coombes","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biomedical Sciences McMaster University  Hamilton ON L8N\u20093Z5 Canada"},{"name":"Michael G. 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