Conformational dynamics, RNA binding, and phase separation regulate the multifunctionality of rabies virus P protein

Stephen M. Rawlinson (), Shatabdi Chakraborty, Ashish Sethi, Cassandra T. David, Angela R. Harrison, Lauren E. Bird, Ashley M. Rozario, Sanjeev Uthishtran, Katie Ardipradja, Tianyue Zhao, Sibil Oksayan, David A. Jans, Ching-Seng Ang, Zhi Hui Lu, Fei Yan, Nicholas A. Williamson, Senthil Arumugam, Vinod Sundaramoorthy, Toby D. M. Bell, Paul R. Gooley () and Gregory W. Moseley ()
Additional contact information
Stephen M. Rawlinson: Monash University
Shatabdi Chakraborty: University of Melbourne
Ashish Sethi: University of Melbourne
Cassandra T. David: Monash University
Angela R. Harrison: Monash University
Lauren E. Bird: Monash University
Ashley M. Rozario: Monash University
Sanjeev Uthishtran: Monash University
Katie Ardipradja: Australian Centre for Disease Preparedness (ACDP)
Tianyue Zhao: Monash University
Sibil Oksayan: Monash University
David A. Jans: Monash University
Ching-Seng Ang: University of Melbourne
Zhi Hui Lu: University of Melbourne
Fei Yan: University of Melbourne
Nicholas A. Williamson: University of Melbourne
Senthil Arumugam: Monash University
Vinod Sundaramoorthy: Australian Centre for Disease Preparedness (ACDP)
Toby D. M. Bell: Monash University
Paul R. Gooley: University of Melbourne
Gregory W. Moseley: Monash University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract RNA viruses encode multifunctional proteins to overcome limited genomic capacity and mediate diverse processes in viral replication and host cell modulation. The rabies virus P gene encodes full-length P1 protein and the truncated isoform, P3, which acquires phenotypes absent from P1, including interactions with cellular membrane-less organelles (MLOs) formed by liquid-liquid phase separation (LLPS). This gain-of-function suggests that isoform multifunctionality arises not only from discrete functions of protein modules/domains, but also from conformational regulation involving interactions of the globular C-terminal domain and N-terminal intrinsically disordered regions (IDRs). The precise mechanisms underlying gain-of-function, however, remain unresolved. Here, we compare the structure and function of P1 and P3, identifying isoform-specific long-range intra-protomer interactions between the IDRs and C-terminal domain that correlate with conformational states, LLPS behavior, and subcellular localization. Mutations in P3 that alter MLO interactions correspondingly modulate these interactions. P1 and P3 can interact with similar/overlapping sets of MLO-associated proteins and have similar LLPS capacity, but only P3 binds RNA, and this interaction correlates with gain-/loss-of-function mutations. Our findings reveal that conformational differences in isoforms regulate LLPS behavior and contribute to protein-RNA interactions, which controls access to host LLPS structures, uncovering a previously unrecognized strategy in P protein multifunctionality.

Date: 2025
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DOI: 10.1038/s41467-025-65223-y

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