Disordered Motifs and Domains in Cell Control Wednesday Speaker Abstracts
How Order and Disorder within Paramyxoviral Nucleoproteins and Phosphoproteins
Orchestrate the Molecular Ballet of Transcription and Replication
Sonia Longhi.
AFMB, UMR 7257, CNRS and Aix-Marseille University, France
The nucleoproteins and phosphoproteins of measles, Nipah and Hendra viruses provide an
excellent model system to study the functional impact of disordered motifs. The non-segmented,
single-stranded RNA genome of these paramyxoviruses is encapsidated by the nucleoprotein (N)
within a helical nucleocapsid. Transcription and replication are carried out onto this
ribonucleoproteic complex by the viral RNA dependent RNA polymerase that consists of a
complex between the large protein (L) and the phosphoprotein (P). The P protein serves as an
essential polymerase co-factor as it allows recruitment of L onto the nucleocapsid template.
Tethering of L relies on the interaction between the C-terminal X domain (XD) of the P protein
and the C-terminal, intrinsically disordered domain (N
TAIL
) of N. This latter is disordered not
only in isolation but also in the context of the nucleocapsid, being partly exposed at the surface
of this latter. Within N
TAIL
, a short motif, serving as molecular recognition element, has been
identified and the mechanisms of its interaction with XD thoroughly investigated. In particular,
we have shown that binding to XD triggers
α
-helical folding of this motif, while the majority of
N
TAIL
remains “fuzzy”. Random mutagenesis studies showed that this motif is poorly evolvable,
implying that its sequence has already been naturally optimized for interaction with XD.
Compared to N, the P protein has a higher modular organization, consisting of alternating
disordered and structured regions. Among these latter is a coiled-coil region responsible for P
multimerization. Using X-ray crystallography and SAXS we recently showed that these coiled-
coil regions exhibit considerable differences in the quaternary structure and in the extent of
disorder. The functional implications of these findings will be discussed.
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