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Previous deletion analysis of Loz1 found a region containing two tandem C<jats:sub>2<\/jats:sub>H<jats:sub>2<\/jats:sub> zinc\u2010fingers and an upstream \u201caccessory domain\u201d rich in histidine, lysine, and arginine residues to be sufficient for zinc\u2010dependent DNA binding and gene repression. Here we report unexpected biophysical properties of this pair of seemingly classical C<jats:sub>2<\/jats:sub>H<jats:sub>2<\/jats:sub> zinc fingers. Isothermal titration calorimetry and NMR spectroscopy reveal two distinct zinc binding events localized to the zinc fingers. NMR spectra reveal complex dynamic behavior in this zinc\u2010responsive region spanning time scales from fast 10<jats:sup>\u221212<\/jats:sup>\u201310<jats:sup>\u221210<\/jats:sup> to slow &gt;10<jats:sup>0<\/jats:sup>\u2009s. Slow exchange due to <jats:italic>cis\u2010trans<\/jats:italic> isomerization of the TGERP linker results in the doubling of many signals in the protein. Conformational exchange on the 10<jats:sup>\u22123<\/jats:sup>\u2009s timescale throughout the first zinc finger distinguishes it from the second and is linked to a weaker affinity for zinc. These findings reveal a mechanism of zinc sensing by Loz1 and illuminate how the protein's rough free\u2010energy landscape enables zinc sensing, DNA binding and regulated gene expression.<\/jats:p>","DOI":"10.1002\/pro.70044","type":"journal-article","created":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T12:44:23Z","timestamp":1737809063000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Conformational dynamics in specialized <scp>C<sub>2<\/sub>H<sub>2<\/sub><\/scp> zinc finger domains enable zinc\u2010responsive gene repression in <i>S. pombe<\/i>"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1392-8226","authenticated-orcid":false,"given":"Vibhuti","family":"Wadhwa","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry Center for RNA Biology The Ohio State University  Columbus Ohio 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