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PreprintCited by 23Circadian rhythm and melatoninLight effects on plantsProtein Structure and Dynamics

The formation of a fuzzy complex in the negative arm regulates the robustness of the circadian clock

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Jankowski, Meaghan S., Griffith, Daniel, Shastry, Divya G., Pelham, Jacqueline F., Ginell, Garrett M., Thomas, Joshua, Karande, Pankaj, Holehouse, Alex S., Hurley, Jennifer M.·2022·Nature Communications
DOI 10.1101/2022.01.04.474980PMC PMC11045787

Preprint — published as 10.1038/s41467-024-47761-z · Paper page

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Abstract

Summary: The circadian clock times cellular processes to the day/night cycle via a Transcription-Translation negative Feedback Loop (TTFL). However, a mechanistic understanding of the negative arm in both the timing of the TTFL and its control of output is lacking. We posited that the formation of negative-arm protein complexes was fundamental to clock regulation stemming from the negative arm. Using a modified peptide microarray approach termed L inear m o tif dis c overy using r at ional d e sign (LOCATE), we characterized the interaction of the disordered negative-arm clock protein FREQUENCY to its partner protein FREQUENCY-Interacting RNA helicase. LOCATE identified a specific Short Linear Motif (SLiM) and interaction “hotspot” as well as positively charged “islands” that mediate electrostatic interactions, suggesting a model where negative arm proteins form a “fuzzy” complex essential for clock timing and robustness. Further analysis revealed that the positively charged islands were an evolutionarily conserved feature in higher eukaryotes and contributed to proper clock function.

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Authors
Jankowski, M. S., Griffith, D., Shastry, D. G., Pelham, J. F., Ginell, G. M., Thomas, J., Karande, P., Holehouse, A. S., & Hurley, J. M.
Affiliations
  • Rensselaer Polytechnic Institute (US)
  • Washington University in St. Louis (US)
Corresponding author
Hurley, Jennifer M.
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2022-01-05
Volume
15
Issue
1
Pages
3523-3523
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2022.01.04.474980
PMC
PMC11045787
OpenAlex
W4395447800
Cited by
23
References
1
Citations by year
2026: 5 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 2
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Science Foundation (2045674, CAREER, 2139839, 1247271)
  • U.S. Department of Health and Human Services (GM128687, EB022546)
  • Longer Life Foundation
  • Rensselaer Polytechnic Institute
  • Dartmouth College
  • National Institutes of Health
  • Directorate for Education and Human Resources (2139839)
  • National Institute of General Medical Sciences (GM067545, GM128687, T32GM067545, R35GM128687)
  • National Institute of Biomedical Imaging and Bioengineering (EB022546, U01EB022546)
  • Division of Graduate Education (2139839)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
circadian clock, intrinsically disordered regions, FRQ, Neurospora crassa, protein-protein interaction
MeSH terms
Amino Acid Sequence, Circadian Rhythm, Fungal Proteins, Mutation, Neurospora crassa, Protein Binding, Gene Expression Regulation, Fungal, Protein Array Analysis, CLOCK Proteins, Circadian Clocks, Intrinsically Disordered Proteins

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