4e5x
From Proteopedia
Crystal structure of a complex between the human adenovirus type 2 E3-19K protein and MHC class I molecule HLA-A2/Tax
Structural highlights
Disease[B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.[1] Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Function[E3GL_ADE06] Binds and retains class I heavy chains in the endoplasmic reticulum during the early period of virus infection, thereby impairing their transport to the cell surface. Also delays the expression of class I alleles that it cannot affect by direct retention. Binds transporters associated with antigen processing (TAP) and acts as a tapasin inhibitor, preventing class I/TAP association. In consequence, infected cells are masked for immune recognition by cytotoxic T-lymphocytes (By similarity). [1A02_HUMAN] Involved in the presentation of foreign antigens to the immune system. [TAX_HTL1F] Transcriptional activator that activates both the viral long terminal repeat (LTR) and cellular promoters via activation of CREB, NF-kappa-B, SRF and AP-1 pathways. Binds to three 21 bp repeat elements located within the LTRs, referred to as Tax-responsive elements (TRE). Binding to TRE requires the interaction with CREB1 and CREBBP. Also induces chromatin remodeling of proviral LTR-mediated gene expression by recruiting the histone acetyl transferases CREBBP and EP300 to the chromatin, which results in histone acetylation. Via its interaction with IKK regulatory subunit IKBKG, Tax-1 persistently stimulates I-kappa-B kinase (IKK), resulting in constitutive activation of the transcription factor NF-kappa-B. Induction of the nuclear expression of members of the NFkB family of transcription factors, which leads to up-regulated expression of many gene promoters containing NFkB motifs. These genes include those encoding IL2, IL15, IL2RA and IL15RA, leading to autocrine IL2/IL2RA and IL15/IL15RA loops. The resulting T-cell proliferation leads to malignant transformation and to the development of adult T-cell leukemia (ATL). IL13, known to be linked to leukemogenesis, is also up-regulated by Tax-1. Interaction with PDZ domain-containing proteins induce IL2-independent growth, which may be a factor in multi-step leukemogenesis. Inhibits the action of at least three cellular tumor suppressors p53/TP53, RB1 and DLG1, and suppresses their abilities to dictate apoptosis in primary cells. Required for viral replication (By similarity). [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. Publication Abstract from PubMedE3-19K binds to and retains MHC class I molecules in the endoplasmic reticulum, suppressing anti-adenovirus activities of T cells. We determined the structure of the adenovirus serotype 2 (Ad2, species C) E3-19K-HLA-A2 complex to 1.95-A resolution. Ad2 E3-19K binds to the N terminus of the HLA-A2 groove, contacting the alpha1, alpha2 and alpha3 domains and beta(2)m. Ad2 E3-19K has a unique structure comprising a large N-terminal domain, formed by two partially overlapping beta-sheets arranged in a V shape, and a C-terminal alpha-helix and tail. The structure reveals determinants in E3-19K and HLA-A2 that are important for complex formation; conservation of some of these determinants in E3-19K proteins of different species and MHC I molecules of different loci suggests a universal binding mode for all E3-19K proteins. Our structure is important for understanding the immunomodulatory function of E3-19K. Crystal structure of adenovirus E3-19K bound to HLA-A2 reveals mechanism for immunomodulation.,Li L, Muzahim Y, Bouvier M Nat Struct Mol Biol. 2012 Nov;19(11):1176-81. doi: 10.1038/nsmb.2396. Epub 2012, Oct 7. PMID:23042604[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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