6fln
Crystal structure of the human TRIM25 coiled-coil and PRYSPRY domains
Structural highlights
Function[TRI25_HUMAN] Functions as a 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.[1] [2] [3] Publication Abstract from PubMedRIG-I is a viral RNA sensor that induces the production of type I interferon (IFN) in response to infection with a variety of viruses. Modification of RIG-I with K63-linked poly-ubiquitin chains, synthesised by TRIM25, is crucial for activation of the RIG-I/MAVS signalling pathway. TRIM25 activity is targeted by influenza A virus non-structural protein 1 (NS1) to suppress IFN production and prevent an efficient host immune response. Here we present structures of the human TRIM25 coiled-coil-PRYSPRY module and of complexes between the TRIM25 coiled-coil domain and NS1. These structures show that binding of NS1 interferes with the correct positioning of the PRYSPRY domain of TRIM25 required for substrate ubiquitination and provide a mechanistic explanation for how NS1 suppresses RIG-I ubiquitination and hence downstream signalling. In contrast, the formation of unanchored K63-linked poly-ubiquitin chains is unchanged by NS1 binding, indicating that RING dimerisation of TRIM25 is not affected by NS1. Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition.,Koliopoulos MG, Lethier M, van der Veen AG, Haubrich K, Hennig J, Kowalinski E, Stevens RV, Martin SR, Reis E Sousa C, Cusack S, Rittinger K Nat Commun. 2018 May 8;9(1):1820. doi: 10.1038/s41467-018-04214-8. PMID:29739942[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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