Abstract
Measles virus is a negative-sense, single-stranded RNA virus belonging to the Mononegavirales order which comprises several human pathogens such as Ebola, Nipah, and Hendra viruses. The phosphoprotein of measles virus is a modular protein consisting of an intrinsically disordered N-terminal domain (Karlin, D., Longhi, S., Receveur, V., and Canard, B. (2002) Virology 296, 251-262) and of a C-terminal moiety (PCT) composed of alternating disordered and globular regions. We report the crystal structure of the extreme C-terminal domain (XD) of measles virus phosphoprotein (aa 459-507) at 1.8 A resolution. We have previously reported that the C-terminal domain of measles virus nucleoprotein, NTAIL, is intrinsically unstructured and undergoes induced folding in the presence of PCT (Longhi, S., Receveur-Brechot, V., Karlin, D., Johansson, K., Darbon, H., Bhella, D., Yeo, R., Finet, S., and Canard, B. (2003) J. Biol. Chem. 278, 18638-18648). Using far-UV circular dichroism, we show that within PCT, XD is the region responsible for the induced folding of NTAIL. The crystal structure of XD consists of three helices, arranged in an anti-parallel triple-helix bundle. The surface of XD formed between helices alpha2 and alpha3 displays a long hydrophobic cleft that might provide a complementary hydrophobic surface to embed and promote folding of the predicted alpha-helix of NTAIL. We present a tentative model of the interaction between XD and NTAIL. These results, beyond presenting the first measles virus protein structure, shed light both on the function of the phosphoprotein at the molecular level and on the process of induced folding.
Highlights
The atomic coordinates and structure factors have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ
We have previously reported that the C-terminal domain of measles virus nucleoprotein, NTAIL, is intrinsically unstructured and undergoes induced folding in the presence of PCT (Longhi, S., Receveur-Brechot, V., Karlin, D., Johansson, K., Darbon, H., Bhella, D., Yeo, R., Finet, S., and Canard, B. (2003) J
Modular Organization of P—The P protein of Measles virus (MV) consists of an N-terminal moiety, poorly conserved Nterminal moiety (PNT), which is responsible for binding to NCORE within the N0-P complex [21], and of a Cterminal moiety, PCT, which is responsible for binding to NTAIL in both N0-P and NNUC-P complexes [9, 29]
Summary
The structure of a slightly shortened form (aa 320 – 433) of the multimerization domain of SeV (P, aa 317– 445) has been solved by x-ray crystallography [32] It forms a very stable coiled-coil buttressed by a bundle of three short ␣-helices. The structure of the protein X of SeV (aa 474 –568) has been solved by NMR [33] It is monomeric and consists of a flexible linker (aa 474 –517) fused to the X domain (XD) (aa 517–568). The induced folding of NTAIL in the presence of its physiological partner opens new perspectives in the structural study of disordered regions within the MV replicative complex. To identify precisely the PCT regions involved in the induced folding of NTAIL and to characterize structurally these complexes, we have analyzed the domain organization of MV P. We present a tentative model of the interaction between XD and NTAIL, which casts light on this widespread and still structurally undefined protein-protein mode of interaction
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