7rg5
Importin alpha3 in complex with p50 NLS
Structural highlights
FunctionIMA3_HUMAN Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. Publication Abstract from PubMedThe MERS coronavirus (MERS-CoV) is a highly pathogenic, emerging virus that produces accessory proteins to antagonize the host innate immune response. The MERS-CoV ORF4b protein has been shown to bind preferentially to the nuclear import adapter IMPalpha3 in infected cells, thereby inhibiting NF-kappaB-dependent innate immune responses. Here, we report high-resolution structures of ORF4b bound to two distinct IMPalpha family members. Each exhibit highly similar binding mechanisms that, in both cases, lack a prototypical Lys bound at their P2 site. Mutations within the NLS region dramatically alter the mechanism of binding, which reverts to the canonical P2 Lys binding mechanism. Mutational studies confirm that the novel binding mechanism is important for its nuclear import, IMPalpha interaction, and inhibition of innate immune signaling pathways. In parallel, we determined structures of the nuclear binding domain of NF-kappaB component p50 bound to both IMPalpha2 and alpha3, demonstrating that p50 overlaps with the ORF4b binding sites, suggesting a basis for inhibition. Our results provide a detailed structural basis that explains how a virus can target the IMPalpha nuclear import adapter to impair immunity, and illustrate how small mutations in ORF4b, like those found in closely related coronaviruses such as HKU5, change the IMPalpha binding mechanism. MERS-CoV ORF4b employs an unusual binding mechanism to target IMPalpha and block innate immunity.,Munasinghe TS, Edwards MR, Tsimbalyuk S, Vogel OA, Smith KM, Stewart M, Foster JK, Bosence LA, Aragao D, Roby JA, Basler CF, Forwood JK Nat Commun. 2022 Mar 25;13(1):1604. doi: 10.1038/s41467-022-28851-2. PMID:35338144[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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