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Cited by 1Protein Structure and DynamicsBiochemical and Structural CharacterizationBacterial Genetics and Biotechnology

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A Designed Zn 2+ Sensor Domain Transmits Binding Information to Transmembrane Histidine Kinases

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Hatstat, A. Katherine, Kormos, Rian, Xu, Vee, Du, Guoming, Liu, Lijun, Zhang, Shao-Qing, DeGrado, William F.·2025·Journal of the American Chemical Society
DOI 10.1021/jacs.5c02273PMC PMC11565981

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Abstract

Abstract Generating stimulus-responsive, allosteric signaling de novo is a significant challenge in protein design. In natural systems like bacterial histidine kinases (HKs), signal transduction occurs when ligand binding initiates a signal that is amplified across biological membranes over long distances to induce large-scale rearrangements and phosphorylation relays. Here, we ask whether our understanding of protein design and multi-domain, intramolecular signaling has progressed sufficiently to enable engineering of a HK with tunable de novo components. We generated de novo metal-binding sensor domains and substituted them for the native sensor domain of a transmembrane HK, affording chimeras that transduce signals initiated from a de novo sensor. Signaling depended on the designed sensor’s stability and the interdomain linker’s phase and length. These results show the usefulness of de novo design to elucidate biochemical mechanisms and principles for design of new signaling systems.

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Metadata

Authors
Hatstat, A. K., Kormos, R., Xu, V., Du, G., Liu, L., Zhang, S.-Q., & DeGrado, W. F.
Affiliations
  • University of California, San Francisco (US)
  • City College of San Francisco (US)
  • Chinese Academy of Sciences (CN)
  • University of Kansas (US)
  • Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science
Corresponding author
  • Hatstat, A. Katherine
  • DeGrado, William F.
ORCID
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2025-05-19
Volume
147
Issue
22
Pages
18770-18782
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/jacs.5c02273
PMC
PMC11565981
OpenAlex
W4410495765
Cited by
1
References
4
Citations by year
2026: 1
FWCI
0.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Key Research and Development Program of China (2024YFA0916800)
  • National Natural Science Foundation of China (22177113)
  • National Institute of General Medical Sciences (F32GM147962, K99GM155611, R35GM122603)
  • National Science Foundation (CHE2108660, MCB2306190)
  • National Defense Science and Engineering Graduate
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
de novo protein design, allosteric communication, intramolecular signal transduction, fusion protein, interdomain linker

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