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Cited by 31Systemic Lupus Erythematosus ResearchDNA and Nucleic Acid ChemistryEnzyme Structure and Function

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Structural features of Dnase1L3 responsible for serum antigen clearance

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McCord, Jon J., Engavale, Minal, Masoumzadeh, Elahe, Villarreal, Johanna, Mapp, Britney, Latham, Michael P., Keyel, Peter A., Sutton, R. Bryan·2022·Communications Biology
DOI 10.1038/s42003-022-03755-5PMC PMC9381713

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Abstract

Autoimmunity develops when extracellular DNA released from dying cells is not cleared from serum. While serum DNA is primarily digested by Dnase1 and Dnase1L3, Dnase1 cannot rescue autoimmunity arising from Dnase1L3 deficiencies. Dnase1L3 uniquely degrades antigenic forms of cell-free DNA, including DNA complexed with lipids and proteins. The distinct activity of Dnase1L3 relies on its unique C-terminal Domain (CTD), but the mechanism is unknown. We used multiple biophysical techniques and functional assays to study the interplay between the core catalytic domain and the CTD. While the core domain resembles Dnase1, there are key structural differences between the two enzymes. First, Dnase1L3 is not inhibited by actin due to multiple differences in the actin recognition site. Second, the CTD augments the ability of the core to bind DNA, thereby facilitating the degradation of complexed DNA. Together, these structural insights will inform the development of Dnase1L3-based therapies for autoimmunity.

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Metadata

Authors
McCord, J. J., Engavale, M., Masoumzadeh, E., Villarreal, J., Mapp, B., Latham, M. P., Keyel, P. A., & Sutton, R. B.
Affiliations
Texas Tech University (US)
Corresponding author
Sutton, R. Bryan
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2022-08-16
Volume
5
Issue
1
Pages
825-825
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-022-03755-5
PMC
PMC9381713
OpenAlex
W4292004599
Cited by
31
References
2
Citations by year
2026: 10 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 1
FWCI
3.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • ThinkTech (Texas Tech University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Lupus Research Alliance (707050)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
DNASE1L3, DNase1, autoimmunity, cell-free DNA, C-terminal domain, DNA binding, DNA degradation, autoimmune disease therapy
MeSH terms
Actins, DNA, Endodeoxyribonucleases

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