An ultraweak interaction in the intrinsically disordered replication machinery is essential for measles virus...

Area of Science:

• Structural biology
• Virology
• Molecular dynamics

Background:

• Measles virus genome encapsidation relies on the phosphoprotein (P) to regulate nucleoprotein (N) monomeric state.
• The function of highly disordered amino-terminal domains (P_NTD) in paramyxoviruses is largely unknown.

Purpose of the Study:

• To elucidate the structure and dynamics of the N⁰P_NTD complex at atomic resolution.
• To understand the role of P_NTD in viral replication.

Main Methods:

• Nuclear magnetic resonance (NMR) spectroscopy, including relaxation dispersion.
• Cell-based minigenome assays.

Main Results:

• Atomic resolution structure and dynamics of the 90-kDa N⁰P_NTD complex were determined.
• An ultraweak N-interaction motif within P_NTD was identified, regulating N binding.
• Mutation of this motif abolished viral transcription and replication.

Conclusions:

• A novel mechanism involving a hidden, dynamic interaction motif in P_NTD controls paramyxoviral replication.
• This mechanism is conserved across Paramyxoviridae, presenting new antiviral drug targets.