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Cited by 2Protein Structure and DynamicsProtein Kinase Regulation and GTPase SignalingGenomics and Chromatin Dynamics

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Signal-regulated Unmasking of Nuclear Localization Motif in the PAS Domain Regulates the Nuclear Translocation of PASK

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Xiao, Michael, Dhungel, Sajina, Azad, Roksana, Favaro, Denize C., Rajesh, Rajaian Pushpabai, Gardner, Kevin H., Kikani, Chintan K.·2024·Journal of Molecular Biology
DOI 10.1016/j.jmb.2023.168433PMC PMC10922792

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Abstract

The ligand-regulated PAS domains are one of the most diverse signal-integrating domains found in proteins from prokaryotes to humans. By biochemically connecting cellular processes with their environment, PAS domains facilitate an appropriate cellular response. PAS domain-containing Kinase (PASK) is an evolutionarily conserved protein kinase that plays important signaling roles in mammalian stem cells to establish stem cell fate. We have shown that the nuclear translocation of PASK is stimulated by differentiation signaling cues in muscle stem cells. However, the mechanistic basis of the regulation of PASK nucleo-cytoplasmic translocation remains unknown. Here, we show that the PAS-A domain of PASK contains a putative monopartite nuclear localization sequence (NLS) motif. This NLS is inhibited in cells through intramolecular association with a short linear motif, termed the PAS Interacting Motif (PIM), found upstream of the kinase domain. This interaction serves to retain PASK in the cytosol in the absence of signaling cues. Consistent with that, we show that metabolic inputs induce PASK nuclear import, likely by disrupting this association. We suggest that a route for such linkage may occur through the PAS-A ligand binding cavity. We show that PIM recruitment and artificial ligand binding to the PAS-A domain occur at neighboring locations that could facilitate metabolic control of the PAS-PIM interaction. Thus, the intramolecular interaction in PASK integrates metabolic signaling cues for nuclear translocation and could be targeted to control the balance between self-renewal and differentiation in stem cells.

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Research works printed but not linked: 26

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Metadata

Authors
Xiao, M., Dhungel, S., Azad, R., Favaro, D. C., Rajesh, R. P., Gardner, K. H., & Kikani, C. K.
Affiliations
  • University of Kentucky (US)
  • The Graduate Center, CUNY (US)
  • CUNY Advanced Science Research Center (US)
Corresponding author
  • Gardner, Kevin H.
  • Kikani, Chintan K.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2024-02
Volume
436
Issue
3
Pages
168433
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2023.168433
PMC
PMC10922792
OpenAlex
W4390531992
Cited by
2
References
2
Citations by year
2025: 1 · 2024: 1
FWCI
0.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (acceptedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR073906)
  • National Institutes of Health
  • National Institute of General Medical Sciences (F31 GM142258, R01 GM106239)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
PASK, PAS domain, nuclear localization signal, nuclear import, intramolecular interactions, metabolic signaling, muscle stem cells, ligand-binding cavity, FG loop

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