Unexpected Structural Requirements for GTPase Activity of the Interferon-induced MxA Protein

Schwemmle, Martin; Richter, Marc François; Herrmann, Christian; Nassar, Nicolas; Staeheli, Peter

doi:10.1074/jbc.270.22.13518

Cited by 61 publications

(60 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our yeast 2-hybrid experiments and cross-linking demonstrate that the dynamin assembly domain dimerizes. The second binding interaction, between the GTPase domain and the assembly domain, is consistent with previous results obtained with proteolytic fragments of dynamin (14) and C-terminal deletions of Mx proteins (25). Our results add to those previous reports by delineating the binding sequences and investigating the nucleotide requirements.…”

Section: Binding Between Dynamin Domains Discovered With the Yeast 2-supporting

confidence: 82%

A Model for Dynamin Self-assembly Based on Binding Between Three Different Protein Domains

Smirnova¹,

Shurland²,

Newman-Smith³

et al. 1999

Journal of Biological Chemistry

123

117

View full text Add to dashboard Cite

Dynamin is a 100-kDa GTPase that assembles into multimeric spirals at the necks of budding clathrin-coated vesicles. We describe three different intramolecular binding interactions that may account for the process of dynamin self-assembly. The first binding interaction is the dimerization of a 100-amino acid segment in the C-terminal half of dynamin. We call this segment the assembly domain, because it appears to be critical for multimerization.

show abstract

Section: Binding Between Dynamin Domains Discovered With the Yeast 2-supporting

confidence: 82%

A Model for Dynamin Self-assembly Based on Binding Between Three Different Protein Domains

Smirnova¹,

Shurland²,

Newman-Smith³

et al. 1999

Journal of Biological Chemistry

123

117

View full text Add to dashboard Cite

show abstract

“…On the other hand, the GED functions as an intramolecular GTP-activating domain: the C-terminal leucine zipper motif (65 to 70 amino acids) in the GED folds back to join the N-terminal GTP-binding domain, forming the enzymatically active center of Mx proteins. Mutants lacking the GED domain have no detectable GTPase activity (69). The C-terminal leucine zipper is evolutionarily conserved, suggesting a vital role in Mx function (Fig.…”

Section: Middle Domain and Gtpase Effector Domainmentioning

confidence: 99%

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

240

156

View full text Add to dashboard Cite

SUMMARY Fifty years after the discovery of the mouse Mx1 gene, researchers are still trying to understand the molecular details of the antiviral mechanisms mediated by Mx proteins. Mx proteins are evolutionarily conserved dynamin-like large GTPases, and GTPase activity is required for their antiviral activity. The expression of Mx genes is controlled by type I and type III interferons. A phylogenetic analysis revealed that Mx genes are present in almost all vertebrates, usually in one to three copies. Mx proteins are best known for inhibiting negative-stranded RNA viruses, but they also inhibit other virus families. Recent structural analyses provide hints about the antiviral mechanisms of Mx proteins, but it is not known how they can suppress such a wide variety of viruses lacking an obvious common molecular pattern. Perhaps they interact with a (partially) symmetrical invading oligomeric structure, such as a viral ribonucleoprotein complex. Such an interaction may be of a fairly low affinity, in line with the broad target specificity of Mx proteins, yet it would be strong enough to instigate Mx oligomerization and ring assembly. Such a model is compatible with the broad “substrate” specificity of Mx proteins: depending on the size of the invading viral ribonucleoprotein complexes that need to be wrapped, the assembly process would consume the necessary amount of Mx precursor molecules. These Mx ring structures might then act as energy-consuming wrenches to disassemble the viral target structure.

show abstract

“…This requirement for C GEDGTPase interactions is likely conserved throughout the dynamin family given the high degree of sequence similarity at this interface. Moreover, a six-amino acid C-terminal deletion of the GED in Mx strongly inhibits its GTPase activity (Schwemmle et al, 1995). Whereas the GTPase-GED interactions are clearly intrapolypeptide in our monomeric GG construct, we cannot rule our interpolypeptide interactions in the context of the full-length tetrameric dynamin.…”

Section: Discussionmentioning

confidence: 95%

An Intramolecular Signaling Element that Modulates Dynamin Function In Vitro and In Vivo

Chappie

Acharya

Liu

et al. 2009

MBoC

View full text Add to dashboard Cite

Dynamin exhibits a high basal rate of GTP hydrolysis that is enhanced by self-assembly on a lipid template. Dynamin's GTPase effector domain (GED) is required for this stimulation, though its mechanism of action is poorly understood. Recent structural work has suggested that GED may physically dock with the GTPase domain to exert its stimulatory effects. To examine how these interactions activate dynamin, we engineered a minimal GTPase-GED fusion protein (GG) that reconstitutes dynamin's basal GTPase activity and utilized it to define the structural framework that mediates GED's association with the GTPase domain. Chemical cross-linking of GG and mutagenesis of full-length dynamin establishes that the GTPase-GED interface is comprised of the N-and C-terminal helices of the GTPase domain and the C-terminus of GED. We further show that this interface is essential for structural stability in full-length dynamin. Finally, we identify mutations in this interface that disrupt assembly-stimulated GTP hydrolysis and dynamin-catalyzed membrane fission in vitro and impair the late stages of clathrin-mediated endocytosis in vivo. These data suggest that the components of the GTPase-GED interface act as an intramolecular signaling module, which we term the bundle signaling element, that can modulate dynamin function in vitro and in vivo.

show abstract

Unexpected Structural Requirements for GTPase Activity of the Interferon-induced MxA Protein

Cited by 61 publications

References 27 publications

A Model for Dynamin Self-assembly Based on Binding Between Three Different Protein Domains

A Model for Dynamin Self-assembly Based on Binding Between Three Different Protein Domains

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

An Intramolecular Signaling Element that Modulates Dynamin Function In Vitro and In Vivo

Contact Info

Product

Resources

About