5ezu
From Proteopedia
Crystal structure of the N-terminal domain of vaccinia virus immunomodulator A46 in complex with myristic acid.
Structural highlights
FunctionA46_VACCW Bcl-2-like protein which disrupts the host immune response by inhibiting the TLR4 signaling pathway leading to NF-kappa-B activation. Targets several host TIR adapters including MYD88, TIRAP, TRIF and TICAM2 thereby blocking NF-kappa-B and TRIF-mediated IRF3 activation. Publication Abstract from PubMedVaccinia virus interferes with early events of the activation pathway of the transcriptional factor NF-kB by binding to numerous host TIR-domain containing adaptor proteins. We have previously determined the X-ray structure of the A46 C-terminal domain; however, the structure and function of the A46 N-terminal domain and its relationship to the C-terminal domain have remained unclear. Here, we biophysically characterize residues 1-83 of the N-terminal domain of A46 and present the X-ray structure at 1.55 A. Crystallographic phases were obtained by a recently developed ab initio method entitled ARCIMBOLDO_BORGES that employs tertiary structure libraries extracted from the Protein Data Bank; data analysis revealed an all beta-sheet structure. This is the first such structure solved by this method which should be applicable to any protein composed entirely of beta-sheets. The A46(1-83) structure itself is a beta-sandwich containing a co-purified molecule of myristic acid inside a hydrophobic pocket and represents a previously unknown lipid-binding fold. Mass spectrometry analysis confirmed the presence of long-chain fatty acids in both N-terminal and full-length A46; mutation of the hydrophobic pocket reduced the lipid content. Using a combination of high resolution X-ray structures of the N- and C-terminal domains and SAXS analysis of full-length protein A46(1-240), we present here a structural model of A46 in a tetrameric assembly. Integrating affinity measurements and structural data, we propose how A46 simultaneously interferes with several TIR-domain containing proteins to inhibit NF-kappaB activation and postulate that A46 employs a bipartite binding arrangement to sequester the host immune adaptors TRAM and MyD88. Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins.,Fedosyuk S, Bezerra GA, Radakovics K, Smith TK, Sammito M, Bobik N, Round A, Ten Eyck LF, Djinovic-Carugo K, Uson I, Skern T PLoS Pathog. 2016 Dec 14;12(12):e1006079. doi: 10.1371/journal.ppat.1006079., eCollection 2016 Dec. PMID:27973613[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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