Intrinsic disorder in measles virus nucleocapsids

The genome of measles virus is encapsidated by multiple copies of the nucleoprotein (N), forming helical nucleocapsids of molecular mass approaching 150 Megadalton. The intrinsically disordered C-terminal domain of N (N-TAIL) is essential for transcription and replication of the virus via interaction with the phosphoprotein P of the viral polymerase complex. The molecular recognition element (MoRE) of N-TAIL that binds P is situated 90 amino acids from the folded RNA-binding domain (N-CORE) of N, raising questions about the functional role of this disordered chain. Here we report the first in situ structural characterization of N-TAIL in the context of the entire N-RNA capsid. Using nuclear magnetic resonance spectroscopy, small angle scattering, and electron microscopy, we demonstrate that N-TAIL is highly flexible in intact nucleocapsids and that the MoRE is in transient interaction with N-CORE. We present a model in which the first 50 disordered amino acids of N-TAIL are conformationally restricted as the chain escapes to the outside of the nucleocapsid via the interstitial space between successive N-CORE helical turns. The model provides a structural framework for understanding the role of N-TAIL in the initiation of viral transcription and replication, placing the flexible MoRE close to the viral RNA and, thus, positioning the polymerase complex in its functional environment.