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PreprintCited by 6Enzyme Structure and FunctionUbiquitin and proteasome pathwaysProtein Structure and Dynamics

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Fusion crystallization reveals the behavior of both the 1TEL crystallization chaperone and the TNK1 UBA domain

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Nawarathnage, Supeshala, Tseng, Yi Jie, Soleimani, Sara, Smith, Tobin, Pedroza Romo, Maria J, Abiodun, Wisdom Oshireku, Egbert, Christina M., Madhusanka, Deshan, Bunn, Derick, Woods, Bridger, Tsubaki, Evan, Stewart, Cameron, Brown, Seth, Doukov, Tzanko, Andersen, Joshua L., Moody, James D.·2023·Structure
DOI 10.1101/2023.06.14.544429PMC PMC10843481

Preprint — published as 10.1016/j.str.2023.09.001 · Paper page

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Abstract

Summary: Human thirty-eight-negative kinase-1 (TNK1) is implicated in cancer progression. The TNK1-UBA domain binds polyubiquitin and plays a regulatory role in TNK1 activity and stability. Sequence analysis suggests an unusual architecture for the TNK1 UBA domain, but an experimentally-validated molecular structure is undetermined. To gain insight into TNK1 regulation, we fused the UBA domain to the 1TEL crystallization chaperone and obtained crystals diffracting as far as 1.53 Å. A 1TEL search model enabled solution of the X-ray phases. GG and GSGG linkers allowed the UBA to reproducibly find a productive binding mode against its host 1TEL polymer and to crystallize at protein concentrations as low as 0.1 mg/mL. Our studies support a mechanism of TELSAM fusion crystallization and show that TELSAM fusion crystals require fewer crystal contacts than traditional protein crystals. Modeling and experimental validation suggest the UBA domain may be selective for both the length and linkages of polyubiquitin chains.

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Metadata

Authors
Nawarathnage, S., Tseng, Y. J., Soleimani, S., Smith, T., Pedroza Romo, M. J., Abiodun, W. O., Egbert, C. M., Madhusanka, D., Bunn, D., Woods, B., Tsubaki, E., Stewart, C., Brown, S., Doukov, T., Andersen, J. L., & Moody, J. D.
Affiliations
  • Brigham Young University (US)
  • Stanford Synchrotron Radiation Lightsource (US)
Corresponding author
  • Andersen, Joshua L.
  • Moody, James D.
ORCID
Venue
Structure
Publisher
openRxiv
Published
2023-06-14
Volume
31
Issue
12
Pages
1589-1603.e6
ISSN
0969-2126 (ISSN-L)
DOI
10.1101/2023.06.14.544429
PMC
PMC10843481
OpenAlex
W4387208815
Cited by
6
References
1
Citations by year
2026: 2 · 2025: 4
FWCI
0.44
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Structure (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Energy (76SF00515, DE–AC02–76SF00515, AC02‐76SF00515, P30-GM133894, DE-AC02-)
  • National Institutes of Health (1r01gm147310-01, NIH-R01, DE-AC02-76SF00515, R01 GM147310-01)
  • Office of Science (AC02-76SF00515, DE-AC02-76SF0051 5, DE-AC02, 76SF00515)
  • National Institute of General Medical Sciences (GM146209, R01GM147310, DE-AC02-76SF00515, R15GM146209, GM147310-01, P30GM133894)
  • Basic Energy Sciences (DE-AC02, 76SF00515, AC02-76SF00515, DE-AC-02-76SF00515)
  • Biological and Environmental Research (DE- AC0276SF00515, P30GM133894)
  • SLAC National Accelerator Laboratory (DEAC02−76SF00515, AC02‐76SF00515)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
TNK1, UBA domain, crystallization chaperones, protein-protein complex structure, crystal contacts, tumor progression

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