7kiu | pdb_00007kiu
Structure of recombinant human DNase1L3 in complex with Mg2+
Structural highlights
DiseaseDNSL3_HUMAN Autosomal systemic lupus erythematosus;Hypocomplementemic urticarial vasculitis. The disease is caused by variants affecting the gene represented in this entry. FunctionDNSL3_HUMAN Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends (By similarity). Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA (PubMed:9070308, PubMed:9714828, PubMed:14646506, PubMed:10807908, PubMed:27293190). Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis (PubMed:23229555, PubMed:24312463). The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells (By similarity). Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity (PubMed:27293190). Together with DNASE1, plays a key role in degrading neutrophil extracellular traps (NETs) (By similarity). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (By similarity). Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation (By similarity).[UniProtKB:O55070][UniProtKB:O89107][1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedAutoimmunity 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. Structural features of Dnase1L3 responsible for serum antigen clearance.,McCord JJ, Engavale M, Masoumzadeh E, Villarreal J, Mapp B, Latham MP, Keyel PA, Sutton RB Commun Biol. 2022 Aug 16;5(1):825. doi: 10.1038/s42003-022-03755-5. PMID:35974043[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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