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

Chappie, Joshua S.; Acharya, Sharmistha; Liu, Ya Wen; Leonard, Marilyn; Pucadyil, Thomas J.; Schmid, Sandra L.

doi:10.1091/mbc.e09-04-0318

Cited by 80 publications

(92 citation statements)

References 42 publications

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“…alytic domain (Chappie et al 2009;Faelber et al 2011;Ford et al 2011;Chappie and Dyda 2013). In human cells, three isoforms-dynamins 1, 2, and 3-drive the pinching off of endocytic-coated vesicles at the plasma membrane, through a cycle of oligomerization and GTP hydrolysis.…”

Section: Synaptojaninmentioning

confidence: 99%

Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic

Kirchhausen

Owen

Harrison

2014

Cold Spring Harbor Perspectives in Biology

411

428

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Clathrin is a molecular scaffold for vesicular uptake of cargo at the plasma membrane, where its assembly into cage-like lattices underlies the clathrin-coated pits of classical endocytosis. This review describes the structures of clathrin, major cargo adaptors, and other proteins that participate in forming a clathrin-coated pit, loading its contents, pinching off the membrane as a lattice-enclosed vesicle, and recycling the components. It integrates as much of the structural information as possible at the time of writing into a sketch of the principal steps in coated-pit and coated-vesicle formation.

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Section: Synaptojaninmentioning

confidence: 99%

Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic

Kirchhausen

Owen

Harrison

2014

Cold Spring Harbor Perspectives in Biology

411

428

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“…The stalk domain harbors the GTPase effector domain and additional structural elements, including the L4 loop required for antiviral activity and target specificity (7)(8)(9). The G and stalk domains are connected via the bundle signaling element (BSE), which strongly resembles the BSE responsible for intramolecular signaling in dynamin (10). Mx proteins exhibit a high intrinsic rate of GTP hydrolysis, although the affinity to GTP is weak (11).…”

mentioning

confidence: 99%

Oligomerization and GTP-binding Requirements of MxA for Viral Target Recognition and Antiviral Activity against Influenza A Virus

Nigg

Pavlovic

2015

Journal of Biological Chemistry

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The IFN-induced human myxovirus resistance protein A (MxA) exhibits a broad antiviral activity against many viruses, including influenza A virus (IAV). MxA belongs to the family of dynamin-like GTPases and assembles in vitro into dimers, tetramers, and oligomeric ring-like structures. The molecular mechanism of action remains to be elucidated. Furthermore, it is not clear whether MxA exerts its antiviral activity in a monomeric and/or multimeric form. Using a set of MxA mutants that form complexes with defined stoichiometry, we observed that, in the presence of guanosine 5-O-(thiotriphosphate), purified MxA disassembled into tetramers and dimers. Dimeric forms did not further disassemble into monomers. Infection experiments revealed that besides wild-type MxA, dimeric and monomeric variants of MxA also efficiently restricted IAV at a replication step after primary transcription. Moreover, only dimeric MxA was able to form stable complexes with the nucleoprotein (NP) of IAV. MxA interacted with NP independently of other viral components. Interestingly, the dimeric form of MxA was able to efficiently bind to NP from several MxA-sensitive strains but interacted much more weakly with NP from the MxA-resistant PR8 strain derived from the H1N1 1918 lineage. Taken together, these data suggest that, during infection, a fraction of MxA disassembles into dimers that bind to NP synthesized following primary transcription in the cytoplasm, thereby preventing viral replication.The interferon system plays a pivotal role in the defense against viral infection. Interferons type I and III induce the expression of more than 300 proteins, many of them exhibiting intrinsic antiviral activity (1-3). The human myxovirus resistance protein A (MxA) 3 protein is induced exclusively by type I and type III interferons and restricts the replication of a large variety of RNA and DNA viruses (reviewed in Ref. 4). Mx proteins are members of the dynamin superfamily of large GTPases. They contain an amino-terminal globular GTPase (G) domain and a carboxy-terminal stalk domain (5, 6). The stalk domain harbors the GTPase effector domain and additional structural elements, including the L4 loop required for antiviral activity and target specificity (7-9). The G and stalk domains are connected via the bundle signaling element (BSE), which strongly resembles the BSE responsible for intramolecular signaling in dynamin (10). Mx proteins exhibit a high intrinsic rate of GTP hydrolysis, although the affinity to GTP is weak (11). Moreover, the human MxA protein forms dimers and tetramers and has the capacity to form higher oligomeric ringlike structures through a series of intra-and intermolecular interactions (5, 6, 12, 13). Introduction of mutations into the interfaces of the intermolecular interaction sites or hinge regions of MxA prevents assembly into higher-order multimeric forms. These mutations lead to the formation of MxA into tetramers, dimers, and monomers (5, 12).So far, little is known about the molecular mechanism of action of the human MxA...

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“…In low-resolution models of dynamin, the middle domain and GED form a stalk-like structure that is involved in self-assembly (6,7). Furthermore, the GED and the C terminus of the G domain form a three-helix bundle, called the bundle signaling element (BSE), which modulates dynamin function (4,8). A recent crystal structure of a minimal G domain-GED fusion protein revealed dimeric G domains in a catalytically competent transition state that was proposed to play a role in the disassembly of dynamin coats from membrane tubes proceeding the fission event (4,9).…”

mentioning

confidence: 99%

Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A

Byrnes

Sondermann

2011

Proc. Natl. Acad. Sci. U.S.A.

153

249

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The large GTPase atlastin belongs to the dynamin superfamily that has been widely implicated in facilitating membrane tubulation, fission, and in select cases, fusion. Mutations spread across atlastin isoform 1 (atlastin-1) have been identified in patients suffering from hereditary spastic paraplegia (HSP), a neurodegenerative disorder affecting motor neuron function in the lower extremities. On a molecular level, atlastin-1 associates with high membrane curvature and fusion events at the endoplasmic reticulum and cis-Golgi. Here we report crystal structures of atlastin-1 comprising the G and middle domains in two different conformations. Although the orientation of the middle domain relative to the G domain is different in the two structures, both reveal dimeric assemblies with a common, GDP-bound G domain dimer. In contrast, dimer formation in solution is observed only in the presence of GTP and transition state analogs, similar to other G proteins that are activated by nucleotide-dependent dimerization. Analyses of solution scattering data suggest that upon nucleotide binding, the protein adopts a somewhat extended, dimeric conformation that is reminiscent of one of the two crystal structures. These structural studies suggest a model for nucleotide-dependent regulation of atlastin with implications for membrane fusion. This mechanism is affected in several mutants associated with HSP, providing insights into disease pathogenesis.protein structure | neuropathogenic mechanism | tubular membrane network

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

Cited by 80 publications

References 42 publications

Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic

Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic

Oligomerization and GTP-binding Requirements of MxA for Viral Target Recognition and Antiviral Activity against Influenza A Virus

Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A

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