Year: 2022
Type: article
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.
Source: Communications Biology
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,490
Funders: U.S. Department of Energy, CH Foundation, Texas Tech University, Lupus Research Alliance, Texas Tech University Health Sciences Center, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory
Awards: G1229526393, G1286251239, G2371548206, G2604287368, G262532246, G303061748, G315621713, G4202012489, G4235786860, G4581610328, G4908923434, G495301720, G498139845, G5570207115, G628751139, G6550344761, G7083997402, G7283024673, G7313278570, G7396808078, G7863156295, G8207748872, G8382000481, G8925327636, A Synchrotron Radiation Structural Biology Resource, Structural Biology Studies of a Large DNA Repair Complex, G911061179, G969889393
OpenAlex ID: W4292004599