4b8e
PRY-SPRY domain of Trim25
Structural highlights
FunctionTRI25_MOUSE Functions as an ubiquitin E3 ligase and as an ISG15 E3 ligase. Involved in innate immune defense against viruses by mediating ubiquitination of DDX58. Mediates 'Lys-63'-linked polyubiquitination of the DDX58 N-terminal CARD-like region which is crucial for triggering the cytosolic signal transduction that leads to the production of interferons in response to viral infection. Promotes ISGylation of 14-3-3 sigma (SFN), an adapter protein implicated in the regulation of a large spectrum signaling pathway. Mediates estrogen action in various target organs (By similarity). Publication Abstract from PubMedTripartite motif (TRIM) proteins primarily function as ubiquitin E3 ligases that regulate the innate immune response to infection. TRIM25 (also known as estrogen-responsive finger protein (Efp)) has been implicated in the regulation of estrogen receptor alpha signaling, and in the regulation of innate immune signaling via retinoic acid-inducible gene-I (RIG-I). RIG-I senses cytosolic viral RNA, and is subsequently ubiquitinated by TRIM25 at its N-terminal CARD domains, leading to type I interferon production. The interaction with RIG-I is dependent on the TRIM25 B30.2 domain, a protein interaction domain composed of the PRY and SPRY tandem sequence motifs. Here we present the 1.8 A crystal structure of the TRIM25 B30.2 domain, which exhibits a typical B30.2/SPRY domain fold comprising two N-terminal alpha-helices, thirteen beta-strands arranged into two beta-sheets, and loop regions of varying lengths. A comparison with other B30.2/SPRY structures and an analysis of the loop regions identified a putative binding pocket, which is likely to be involved in binding target proteins. This was supported by mutagenesis and functional analyses, which identified two key residues (Asp-488, Trp-621) in the TRIM25 B30.2 domain as being critical for binding to the RIG-I CARD domains. Crystal Structure of the TRIM25 B30.2 (PRYSPRY) domain: A Key Component of Antiviral Signaling.,D'Cruz AA, Kershaw NJ, Chiang JJ, Wang MK, Nicola NA, Babon JJ, Gack MU, Nicholson SE Biochem J. 2013 Sep 10. PMID:24015671[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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