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Structural features of Dnase1L3 responsible for serum antigen clearance

Journal Article · · Communications Biology
 [1];  [2];  [3];  [4];  [2];  [3];  [2];  [4]
  1. Texas Tech Univ., Lubbock, TX (United States). Health Sciences Center. Dept. of Cell Physiology and Molecular Biophysics; OSTI
  2. Texas Tech Univ., Lubbock, TX (United States). Dept. of Biological Sciences
  3. Texas Tech Univ., Lubbock, TX (United States). Dept. of Chemistry & Biochemistry
  4. Texas Tech Univ., Lubbock, TX (United States). Health Sciences Center. Dept. of Cell Physiology and Molecular Biophysics

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.

Research Organization:
SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1903977
Journal Information:
Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 5; ISSN 2399-3642
Publisher:
Springer NatureCopyright Statement
Country of Publication:
United States
Language:
English

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