7rlo | pdb_00007rlo
Structure of the human eukaryotic translation initiation factor 2B (eIF2B) in complex with a viral protein NSs
Structural highlights
DiseaseEI2BE_HUMAN Defects in EIF2B5 are a cause of leukodystrophy with vanishing white matter (VWM) [MIM:603896. VWM is a leukodystrophy that occurs mainly in children. Neurological signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy and relatively preserved mental abilities. The disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. While childhood onset is the most common form of the disorder, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree leukoencephalopathy. Milder forms may not become evident until adolescence or adulthood. Some females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.[1] [2] [3] [4] [5] [6] FunctionEI2BE_HUMAN Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. Publication Abstract from PubMedViral infection triggers activation of the integrated stress response (ISR). In response to viral double-stranded RNA (dsRNA), RNA-activated protein kinase (PKR) phosphorylates the translation initiation factor eIF2, converting it from a translation initiator into a potent translation inhibitor and this restricts the synthesis of viral proteins. Phosphorylated eIF2 (eIF2-P) inhibits translation by binding to eIF2's dedicated, heterodecameric nucleotide exchange factor eIF2B and conformationally inactivating it. We show that the NSs protein of Sandfly Fever Sicilian virus (SFSV) allows the virus to evade the ISR. Mechanistically, NSs tightly binds to eIF2B (K(D )= 30 nM), blocks eIF2-P binding, and rescues eIF2B GEF activity. Cryo-EM structures demonstrate that SFSV NSs and eIF2-P directly compete, with the primary NSs contacts to eIF2Balpha mediated by five 'aromatic fingers'. NSs binding preserves eIF2B activity by maintaining eIF2B's conformation in its active A-State. Viral evasion of the integrated stress response through antagonism of eIF2-P binding to eIF2B.,Schoof M, Wang L, Cogan JZ, Lawrence RE, Boone M, Wuerth JD, Frost A, Walter P Nat Commun. 2021 Dec 7;12(1):7103. doi: 10.1038/s41467-021-26164-4. PMID:34876554[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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