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Mx Proteins: Large GTPases Involved in Host Defense against RNA viruses

Investigators:

Alex von der Malsburg	Simone Gruber	Otto Haller	Georg Kochs	Corinna Patzina

In collaboration with:

• Dr. Oliver Daumke, MDC-Berlin: Structural analysis of Mx proteins
• Dr. Dganit Danino, Technion, Haifa, Israel: Cryoelectronmicroscopic analysis of Mx oligomers and Mx membrane interactions.
• Prof. M. Schwemmle, Department of Virology, Freiburg: Identification of Mx-associated cellular factors.

Abstract

Mx proteins are key antiviral effector molecules which are induced by type I (alpha/beta) and type III (lambda) interferons and block an early step in the life cycle of specific human and animal viruses. They belong to the dynamin family of large GTPases and consist of three functional domains, namely (i) the aminoterminal “G domain” that binds and hydrolyses GTP, (ii) the “bundle signalling element” and (iii) the “stalk” which mediates oligomerization and is composed of the middle domain (MD) and the carboxyterminal GTPase effector domain (GED). Importantly, Mx proteins have an intrinsic, cell-autonomous antiviral activity which depends on proper oligomerization. Available data indicate that Mx proteins work like pathogen-associated pattern-recognition (PAMP) receptors and oligomerize around viral nucleocapsids, thereby blocking their function. Recently, the crystal structure of the MxA stalk mediating oligomerization was solved. In future projects we want to characterize the physical interaction of Mx proteins with the viral target structure(s) and define the critical interaction domains. A long-term goal is to use the Mx - virus interaction platform as a blue-pint for novel antiviral substances.

Please click on image to enlarge Oligomerizetion of human MxA. Model of oligomeric MxA composed of the MxA stalks connected to the G domains of dynamin. Side (a) and front views (b) are shown. MxA ring (c) composed of 16 MxA dimers is designed according to cryo-EM reconstructions of dynamin. For details see Gao et al. Nature 465: 502-506 (2010).

Selected References

1. Haller, O., Stertz, S., Kochs, G.
   The Mx GTPase family of interferon-induced antiviral protein
   Microbes and Infection 9: 1636-1643 (2007) (review)
2. Haller, O., Gao, S., von der Malsburg, A., Daumke, O., Kochs, G.
   Dynamin-like MxA GTPase: Structural insights into oligomerization and implications for antiviral activity.
   J Biol Chem 285: 28419-28424 (2010) (minireview)
3. Gao, S., Von der Malsburg, A., Paeschke, S., Behlke, J., Haller, O., Kochs, G., Daumke, O.
   Structural basis of oligomerization in the stalk region of dynamin-like MxA.
   Nature 465: 502-506 (2010)
4. Dittmann, J., Stertz, S., Grimm, D., Steel, J., García-Sastre, A., Haller, O., and Kochs, G.
   Influenza A virus strains differ in sensitivity to the antiviral action of the Mx-GTPase.
   J. Virol. 82: 3624-3631 (2008).
5. Grimm, D., Staeheli, P., Hufbauer, M., Koerner, I., Martínez-Sobrido, L., Solórzano, A., García-Sastre, A., Haller, O., Kochs, G.
   Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene.
   Proc Natl Acad Sci Proc Natl Acad Sci 104:6806-6811 (2007)
6. Tumpey, T.M., Szretter, K.J., Van Hoeven, N., Katz, J.M, Kochs, G., Haller, O., García-Sastre, A., Staeheli, P.
   The Mx1 gene protects mice against the pandemic 1918 and highly lethal human H5N1 influenza viruses.
   J Virol 81: 10818-10821 (2007)
7. Holzinger, D., Jorns, C., Stertz, S., Boisson-Dupuis, S., Thimme, R., Weidmann, M., Casanova, J.-L., Haller, O., Kochs, G.
   Induction of MxA gene expression by influenza A virus requires type I or type III interferon signaling.
   J Virol 81: 7776-7785 (2007)

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