Conformational dynamics in specialized C₂H₂ zinc finger domains enable zinc-responsive gene repression in S. pombe.

IF 4.5 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Protein Science Pub Date : 2025-02-01 DOI:10.1002/pro.70044

Vibhuti Wadhwa, Cameron Jamshidi, Kye Stachowski, Amanda J Bird, Mark P Foster

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引用次数: 0

Abstract

Loz1 is a zinc-responsive transcription factor in fission yeast that maintains cellular zinc homeostasis by repressing the expression of genes required for zinc uptake in high zinc conditions. Previous deletion analysis of Loz1 found a region containing two tandem C₂H₂ zinc-fingers and an upstream "accessory domain" rich in histidine, lysine, and arginine residues to be sufficient for zinc-dependent DNA binding and gene repression. Here we report unexpected biophysical properties of this pair of seemingly classical C₂H₂ 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-responsive region spanning time scales from fast 10^-12-10^-10 to slow >10⁰ s. Slow exchange due to cis-trans isomerization of the TGERP linker results in the doubling of many signals in the protein. Conformational exchange on the 10^-3 s 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-energy landscape enables zinc sensing, DNA binding and regulated gene expression.

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来源期刊

Protein Science 生物-生化与分子生物学

CiteScore

12.40

自引率

1.20%

发文量

246

审稿时长

1 months

期刊介绍： Protein Science, the flagship journal of The Protein Society, is a publication that focuses on advancing fundamental knowledge in the field of protein molecules. The journal welcomes original reports and review articles that contribute to our understanding of protein function, structure, folding, design, and evolution. Additionally, Protein Science encourages papers that explore the applications of protein science in various areas such as therapeutics, protein-based biomaterials, bionanotechnology, synthetic biology, and bioelectronics. The journal accepts manuscript submissions in any suitable format for review, with the requirement of converting the manuscript to journal-style format only upon acceptance for publication. Protein Science is indexed and abstracted in numerous databases, including the Agricultural & Environmental Science Database (ProQuest), Biological Science Database (ProQuest), CAS: Chemical Abstracts Service (ACS), Embase (Elsevier), Health & Medical Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Database (ProQuest), MEDLINE/PubMed (NLM), Natural Science Collection (ProQuest), and SciTech Premium Collection (ProQuest).