Nature Communications (Apr 2024)

Structural basis for dimerization of a paramyxovirus polymerase complex

  • Jin Xie,
  • Mohamed Ouizougun-Oubari,
  • Li Wang,
  • Guanglei Zhai,
  • Daitze Wu,
  • Zhaohu Lin,
  • Manfu Wang,
  • Barbara Ludeke,
  • Xiaodong Yan,
  • Tobias Nilsson,
  • Lu Gao,
  • Xinyi Huang,
  • Rachel Fearns,
  • Shuai Chen

DOI
https://doi.org/10.1038/s41467-024-47470-7
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 14

Abstract

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Abstract The transcription and replication processes of non-segmented, negative-strand RNA viruses (nsNSVs) are catalyzed by a multi-functional polymerase complex composed of the large protein (L) and a cofactor protein, such as phosphoprotein (P). Previous studies have shown that the nsNSV polymerase can adopt a dimeric form, however, the structure of the dimer and its function are poorly understood. Here we determine a 2.7 Å cryo-EM structure of human parainfluenza virus type 3 (hPIV3) L–P complex with the connector domain (CD′) of a second L built, while reconstruction of the rest of the second L–P obtains a low-resolution map of the ring-like L core region. This study reveals detailed atomic features of nsNSV polymerase active site and distinct conformation of hPIV3 L with a unique β-strand latch. Furthermore, we report the structural basis of L–L dimerization, with CD′ located at the putative template entry of the adjoining L. Disruption of the L–L interface causes a defect in RNA replication that can be overcome by complementation, demonstrating that L dimerization is necessary for hPIV3 genome replication. These findings provide further insight into how nsNSV polymerases perform their functions, and suggest a new avenue for rational drug design.