6t3x
Crystal structure of the truncated human cytomegalovirus pUL50-pUL53 complexCrystal structure of the truncated human cytomegalovirus pUL50-pUL53 complex
Structural highlights
FunctionNEC2_HCMVA Plays an essential role in virion nuclear egress, the first step of virion release from infected cell. Within the host nucleus, NEC1 interacts with the newly formed capsid through the vertexes and directs it to the inner nuclear membrane by associating with NEC2. Induces the budding of the capsid at the inner nuclear membrane as well as its envelopment into the perinuclear space. There, the NEC1/NEC2 complex promotes the fusion of the enveloped capsid with the outer nuclear membrane and the subsequent release of the viral capsid into the cytoplasm where it will reach the secondary budding sites in the host Golgi or trans-Golgi network.[HAMAP-Rule:MF_04024]NEC1_HCMVA Plays an essential role in virion nuclear egress, the first step of virion release from infected cell. Within the host nucleus, NEC1 interacts with the newly formed capsid through the vertexes and directs it to the inner nuclear membrane by associating with NEC2. Induces the budding of the capsid at the inner nuclear membrane as well as its envelopment into the perinuclear space. There, the NEC1/NEC2 complex promotes the fusion of the enveloped capsid with the outer nuclear membrane and the subsequent release of the viral capsid into the cytoplasm where it will reach the secondary budding sites in the host Golgi or trans-Golgi network.[HAMAP-Rule:MF_04023][1] Publication Abstract from PubMedHerpesviruses uniquely express two essential nuclear egress-regulating proteins forming a heterodimeric basic structure of the nuclear-egress complex (core NEC). These core NECs serve as a hexameric lattice-structured platform for capsid docking and recruit viral and cellular NEC-associated factors that jointly exert nuclear lamina- and membrane-rearranging functions (multicomponent NEC). Here, we report the X-ray structures of beta- and gamma-herpesvirus core NECs obtained through an innovative recombinant expression strategy based on NEC-hook::NEC-groove protein fusion constructs. This approach yielded the first structure of gamma-herpesviral core NEC, namely the 1.56 A structure of Epstein-Barr virus (EBV) BFRF1-BFLF2, as well as an increased resolution 1.48 A structure of human cytomegalovirus (HCMV) pUL50-pUL53. Detailed analysis of these structures revealed that the prominent hook segment is absolutely required for core NEC formation and contributes approx. 80% of the interaction surface of the globular domains of NEC proteins. Moreover, using HCMV::EBV hook domain swap constructs, computational prediction of the roles of individual hook residues for binding, and quantitative binding assays with synthetic peptides presenting the HCMV- and EBV-specific NEC hook sequences, we characterized the unique hook-into-groove NEC interaction at various levels. Although the overall physicochemical characteristics of the protein interfaces differ considerably in these beta- and gamma-herpesvirus NECs, the binding free energy contributions of residues displayed from identical positions are similar. In summary, the results of our study reveal critical details of the molecular mechanism of herpesviral NEC interactions and highlight their potential as an antiviral drug target. High-resolution crystal structures of two prototypical beta- and gamma-herpesviral nuclear egress complexes unravel the determinants of subfamily specificity.,Muller YA, Hage S, Alkhashrom S, Hollriegl T, Weigert S, Dolles S, Hof K, Walzer SA, Egerer-Sieber C, Conrad M, Holst S, Losing J, Sonntag E, Sticht H, Eichler J, Marschall M J Biol Chem. 2020 Jan 24. pii: RA119.011546. doi: 10.1074/jbc.RA119.011546. PMID:31980459[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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