The Experts below are selected from a list of 339 Experts worldwide ranked by ideXlab platform
H Schuler - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the atpase Domain of the human AAA protein paraplegin spg7
PLOS ONE, 2009Co-Authors: T Karlberg, Susanne Van Den Berg, Martin Hammarstrom, J Sagemark, Ida Johansson, L Holmbergschiavone, H SchulerAbstract:Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic paraplegias. The gene encodes an FtsH-homology protease Domain in tandem with an AAA+ homology ATPase Domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-Domain to deliver substrate peptides to its protease Domain. We present the crystal structure of the AAA-Domain of human paraplegin bound to ADP at 2.2 A. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations.
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crystal structure of the atpase Domain of the human AAA protein paraplegin spg7
PLOS ONE, 2009Co-Authors: T Karlberg, Martin Hammarstrom, J Sagemark, Ida Johansson, L Holmbergschiavone, Susanne Van Den Berg, H SchulerAbstract:Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic paraplegias. The gene encodes an FtsH-homology protease Domain in tandem with an AAA+ homology ATPase Domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-Domain to deliver substrate peptides to its protease Domain. We present the crystal structure of the AAA-Domain of human paraplegin bound to ADP at 2.2 A. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations. Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Ronald D Vale - One of the best experts on this subject based on the ideXlab platform.
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structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin
Nature, 2008Co-Authors: Antonina Rollmecak, Ronald D ValeAbstract:Spastin, a microtubule severing protein involved in the assembly or function of nuclear protein complexes, has attracted interest because of its role in neuronal synapse formation, and the discovery that mutations in the gene cause hereditary neurodegenerative disease. The structure of spastin has now been determined to atomic resolution by X-ray crystallography, revealing an AAA ATPase cassette augmented by structural elements unique to the microtubule severing enzyme subfamily. Mapping of hereditary spastic paraplegia mutations onto the structure of spastin reveals how disease mutations damage the enzyme. Spastin and kastin are AAA-ATPases that function as microtubule severing enzymes. Mutations in spastin are the predominant cause of hereditary spastic paraplegias (HSP). The atomic structure of spastin monomer and coupled with atomic docking generate a model of spastin hexamer is solved. Spastin forms a ring with a prominent central pore and six radiating arms that dock onto the microtubule. Spastin, the most common locus for mutations in hereditary spastic paraplegias1, and katanin are related microtubule-severing AAA ATPases2,3,4,5,6 involved in constructing neuronal7,8,9,10 and non-centrosomal7,11 microtubule arrays and in segregating chromosomes12,13. The mechanism by which spastin and katanin break and destabilize microtubules is unknown, in part owing to the lack of structural information on these enzymes. Here we report the X-ray crystal structure of the Drosophila spastin AAA Domain and provide a model for the active spastin hexamer generated using small-angle X-ray scattering combined with atomic docking. The spastin hexamer forms a ring with a prominent central pore and six radiating arms that may dock onto the microtubule. Helices unique to the microtubule-severing AAA ATPases surround the entrances to the pore on either side of the ring, and three highly conserved loops line the pore lumen. Mutagenesis reveals essential roles for these structural elements in the severing reaction. Peptide and antibody inhibition experiments further show that spastin may dismantle microtubules by recognizing specific features in the carboxy-terminal tail of tubulin. Collectively, our data support a model in which spastin pulls the C terminus of tubulin through its central pore, generating a mechanical force that destabilizes tubulin–tubulin interactions within the microtubule lattice. Our work also provides insights into the structural defects in spastin that arise from mutations identified in hereditary spastic paraplegia patients.
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structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin
Nature, 2008Co-Authors: Antonina Rollmecak, Ronald D ValeAbstract:Spastin, the most common locus for mutations in hereditary spastic paraplegias, and katanin are related microtubule-severing AAA ATPases involved in constructing neuronal and non-centrosomal microtubule arrays and in segregating chromosomes. The mechanism by which spastin and katanin break and destabilize microtubules is unknown, in part owing to the lack of structural information on these enzymes. Here we report the X-ray crystal structure of the Drosophila spastin AAA Domain and provide a model for the active spastin hexamer generated using small-angle X-ray scattering combined with atomic docking. The spastin hexamer forms a ring with a prominent central pore and six radiating arms that may dock onto the microtubule. Helices unique to the microtubule-severing AAA ATPases surround the entrances to the pore on either side of the ring, and three highly conserved loops line the pore lumen. Mutagenesis reveals essential roles for these structural elements in the severing reaction. Peptide and antibody inhibition experiments further show that spastin may dismantle microtubules by recognizing specific features in the carboxy-terminal tail of tubulin. Collectively, our data support a model in which spastin pulls the C terminus of tubulin through its central pore, generating a mechanical force that destabilizes tubulin-tubulin interactions within the microtubule lattice. Our work also provides insights into the structural defects in spastin that arise from mutations identified in hereditary spastic paraplegia patients.
Anthony J Wilkinson - One of the best experts on this subject based on the ideXlab platform.
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the crystal structure of the AAA Domain of the atp dependent protease ftsh of escherichia coli at 1 5 a resolution
Structure, 2002Co-Authors: Szymon Krzywda, Andrzej M Brzozowski, Kiyonobu Karata, Teru Ogura, Chandra S Verma, Anthony J WilkinsonAbstract:Eubacteria and eukaryotic cellular organelles have membrane-bound ATP-dependent proteases, which degrade misassembled membrane protein complexes and play a vital role in membrane quality control. The bacterial protease FtsH also degrades an interesting subset of cytoplasmic regulatory proteins, including σ32, LpxC, and λ CII. The crystal structure of the ATPase module of FtsH has been solved, revealing an α/β nucleotide binding Domain connected to a four-helix bundle, similar to the AAA modules of proteins involved in DNA replication and membrane fusion. A sulfate anion in the ATP binding pocket mimics the β-phosphate group of an adenine nucleotide. A hexamer form of FtsH has been modeled, providing insights into possible modes of nucleotide binding and intersubunit catalysis.
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crystallization of the AAA Domain of the atp dependent protease ftsh of escherichia coli
Acta Crystallographica Section D-biological Crystallography, 2002Co-Authors: Szymon Krzywda, Andrzej M Brzozowski, Kiyonobu Karata, Teru Ogura, Anthony J WilkinsonAbstract:FtsH is a membrane-anchored ATP-dependent protease that degrades misfolded or misassembled membrane proteins as well as a subset of cytoplasmic regulatory proteins. It belongs to the family of AAA+ ATPases with roles in diverse cellular processes. The ATPase Domain of FtsH from Escherichia coli has been crystallized from ammonium sulfate solutions and crystals diffracting to 1.5 A resolution have been obtained.
T Karlberg - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the atpase Domain of the human AAA protein paraplegin spg7
PLOS ONE, 2009Co-Authors: T Karlberg, Susanne Van Den Berg, Martin Hammarstrom, J Sagemark, Ida Johansson, L Holmbergschiavone, H SchulerAbstract:Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic paraplegias. The gene encodes an FtsH-homology protease Domain in tandem with an AAA+ homology ATPase Domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-Domain to deliver substrate peptides to its protease Domain. We present the crystal structure of the AAA-Domain of human paraplegin bound to ADP at 2.2 A. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations.
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crystal structure of the atpase Domain of the human AAA protein paraplegin spg7
PLOS ONE, 2009Co-Authors: T Karlberg, Martin Hammarstrom, J Sagemark, Ida Johansson, L Holmbergschiavone, Susanne Van Den Berg, H SchulerAbstract:Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic paraplegias. The gene encodes an FtsH-homology protease Domain in tandem with an AAA+ homology ATPase Domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-Domain to deliver substrate peptides to its protease Domain. We present the crystal structure of the AAA-Domain of human paraplegin bound to ADP at 2.2 A. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations. Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Antonina Rollmecak - One of the best experts on this subject based on the ideXlab platform.
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structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin
Nature, 2008Co-Authors: Antonina Rollmecak, Ronald D ValeAbstract:Spastin, a microtubule severing protein involved in the assembly or function of nuclear protein complexes, has attracted interest because of its role in neuronal synapse formation, and the discovery that mutations in the gene cause hereditary neurodegenerative disease. The structure of spastin has now been determined to atomic resolution by X-ray crystallography, revealing an AAA ATPase cassette augmented by structural elements unique to the microtubule severing enzyme subfamily. Mapping of hereditary spastic paraplegia mutations onto the structure of spastin reveals how disease mutations damage the enzyme. Spastin and kastin are AAA-ATPases that function as microtubule severing enzymes. Mutations in spastin are the predominant cause of hereditary spastic paraplegias (HSP). The atomic structure of spastin monomer and coupled with atomic docking generate a model of spastin hexamer is solved. Spastin forms a ring with a prominent central pore and six radiating arms that dock onto the microtubule. Spastin, the most common locus for mutations in hereditary spastic paraplegias1, and katanin are related microtubule-severing AAA ATPases2,3,4,5,6 involved in constructing neuronal7,8,9,10 and non-centrosomal7,11 microtubule arrays and in segregating chromosomes12,13. The mechanism by which spastin and katanin break and destabilize microtubules is unknown, in part owing to the lack of structural information on these enzymes. Here we report the X-ray crystal structure of the Drosophila spastin AAA Domain and provide a model for the active spastin hexamer generated using small-angle X-ray scattering combined with atomic docking. The spastin hexamer forms a ring with a prominent central pore and six radiating arms that may dock onto the microtubule. Helices unique to the microtubule-severing AAA ATPases surround the entrances to the pore on either side of the ring, and three highly conserved loops line the pore lumen. Mutagenesis reveals essential roles for these structural elements in the severing reaction. Peptide and antibody inhibition experiments further show that spastin may dismantle microtubules by recognizing specific features in the carboxy-terminal tail of tubulin. Collectively, our data support a model in which spastin pulls the C terminus of tubulin through its central pore, generating a mechanical force that destabilizes tubulin–tubulin interactions within the microtubule lattice. Our work also provides insights into the structural defects in spastin that arise from mutations identified in hereditary spastic paraplegia patients.
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structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin
Nature, 2008Co-Authors: Antonina Rollmecak, Ronald D ValeAbstract:Spastin, the most common locus for mutations in hereditary spastic paraplegias, and katanin are related microtubule-severing AAA ATPases involved in constructing neuronal and non-centrosomal microtubule arrays and in segregating chromosomes. The mechanism by which spastin and katanin break and destabilize microtubules is unknown, in part owing to the lack of structural information on these enzymes. Here we report the X-ray crystal structure of the Drosophila spastin AAA Domain and provide a model for the active spastin hexamer generated using small-angle X-ray scattering combined with atomic docking. The spastin hexamer forms a ring with a prominent central pore and six radiating arms that may dock onto the microtubule. Helices unique to the microtubule-severing AAA ATPases surround the entrances to the pore on either side of the ring, and three highly conserved loops line the pore lumen. Mutagenesis reveals essential roles for these structural elements in the severing reaction. Peptide and antibody inhibition experiments further show that spastin may dismantle microtubules by recognizing specific features in the carboxy-terminal tail of tubulin. Collectively, our data support a model in which spastin pulls the C terminus of tubulin through its central pore, generating a mechanical force that destabilizes tubulin-tubulin interactions within the microtubule lattice. Our work also provides insights into the structural defects in spastin that arise from mutations identified in hereditary spastic paraplegia patients.
