Abstract
Avian influenza polymerase undergoes host adaptation in order to efficiently replicate in human cells. Adaptive mutants are localised on the C-terminal (627-NLS) domains of the PB2 subunit. In particular, mutation of PB2 residue 627 from E to K rescues polymerase activity in mammalian cells. A host transcription regulator ANP32A, comprising a long C-terminal intrinsically disordered domain (IDD), is responsible for this adaptation. Human ANP32A IDD lacks a 33 residue insertion compared to avian ANP32A, and this deletion restricts avian influenza polymerase activity. We used NMR to determine conformational ensembles of E627 and K627 forms of 627-NLS of PB2 in complex with avian and human ANP32A. Human ANP32A IDD transiently binds to the 627 domain, exploiting multivalency to maximise affinity. E627 interrupts the polyvalency of the interaction, an effect compensated by an avian-unique motif in the IDD. The observed binding mode is maintained in the context of heterotrimeric influenza polymerase, placing ANP32A in the immediate vicinity of known host-adaptive PB2 mutants.
Highlights
Avian influenza polymerase undergoes host adaptation in order to efficiently replicate in human cells
Recent studies demonstrate that the interaction occurs in the nucleus[24], and further studies point to the importance of related members of the ANP32 family, in particular ANP32B20–22, as well as the role of surface residues in the folded leucine-rich region (LRR) of ANP32A23
The intrinsically disordered domain (IDD) of h and avANP32A comprise 63/96 and 79/129 Asp or Glu residues, respectively, leading to extensive spectral overlap. h and avANP32A IDDs differ principally due to a 33 amino acid insert in avANP32A (176–209) comprising an av-unique hexapeptide, 176VLSLVK181, followed by a duplication of 27 amino acids present in Human ANP32A (hANP32A) IDD
Summary
Avian influenza polymerase undergoes host adaptation in order to efficiently replicate in human cells. Most influenza strains evolve exclusively in the large reservoir of water birds, but some highly pathogenic avian strains (e.g., H5N1, H5N8 and H7N9) can infect humans with lethal consequences (up to 60% mortality) and are potential pandemic threats for humanity if they develop human-to-human transmissability[2] For these avian (av) viruses to efficiently replicate in mammalian cells, host adaptation of the viral polymerase is necessary. Human ANP32A (hANP32A) lacks an insertion of 33 disordered residues compared to avANP32A, restricting avH5N1 polymerase activity in mammalian cells. This restriction is lifted by E627K mutation, suggesting an essential role for ANP32A through interaction with PB214–24, there are currently no molecular descriptions of these interactions. We show that the interaction exhibits the same properties in the presence of heterotrimeric influenza polymerase, providing insight into the role of the IDD in the function of putative ANP32A:polymerase complexes
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