Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia

Zhao, Xinping; Alvarado, David M.; Rainier, Shirley; Lemons, Rosemary; Hedera, Peter; Weber, Christian; Tükel, Turgut; Apak, Memnune Yüksel; Heiman‐Patterson, Terry; Lei, Ming; Bui, Melanie; Fink, John K.

doi:10.1038/ng758

Cited by 314 publications

(289 citation statements)

References 28 publications

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“…1A). Like spastin, atlastin is an autosomal dominant HSP gene (12). Atlastin is a Golgi-localized integral membrane protein GTPase (13).…”

Section: Resultsmentioning

confidence: 99%

“…Spastin's MIT binds CHMP1B (11), one of a family of proteins implicated in the multivesicular body pathway. Mutations in atlastin (12), an integral membrane protein GTPase that is primarily localized to the Golgi apparatus (13), also cause HSP. Mutations in alsin, which has Rab 5 and Rac guanine nucleotide exchange domains, suggest that a defect in intracellular trafficking may cause HSP (14,15).…”

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confidence: 99%

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Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance

Evans

Keller

Pavur

et al. 2006

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

112

107

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Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder that is characterized by retrograde axonal degeneration that primarily affects long spinal neurons. The disease is clinically heterogeneous, and there are >20 genetic loci identified. Here, we show a physical interaction between spastin and atlastin, two autosomal dominant HSP gene products. Spastin encodes a microtubule (MT)-severing AAA ATPase (ATPase associated with various activities), and atlastin encodes a Golgi-localized integral membrane protein GTPase. Atlastin does not regulate the enzymatic activity of spastin. We also identified a clinical mutation in atlastin outside of the GTPase domain that prevents interaction with spastin in cells. Therefore, we hypothesize that failure of appropriate interaction between these two HSP gene products may be pathogenetically relevant. These data indicate that at least a subset of HSP genes may define a cellular biological pathway that is important in axonal maintenance.microtubule ͉ AAA ATPase ͉ microtubule severing

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“…1A). Like spastin, atlastin is an autosomal dominant HSP gene (12). Atlastin is a Golgi-localized integral membrane protein GTPase (13).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance

Evans

Keller

Pavur

et al. 2006

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

112

107

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show abstract

“…Atlastin, a large G protein most closely related to the GBP subfamily, has been identified as a crucial protein in maintaining endoplasmic reticulum (ER) morphology and vesicle trafficking (13)(14)(15)(16)(17). Atlastin lacks a GED but instead contains two transmembrane helices and a C-terminal domain in addition to its large G and middle domains, both of which face the cytoplasm (18).…”

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.

154

260

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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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“…It is highly expressed in the regions of the brain studied so far, including the cortex, while expression in other organs is much lower (26). Atlastin has a molecular mass of 63.4 kD and contains three conserved motives, a P-Loop, DxxG and RD, typical for guanylate binding/GTPase activity sites.…”

Section: Atlastin and Kinesinmentioning

confidence: 99%

Hereditary Spastic Paraplegia: Clues from a Rare Disorder for a Common Problem?

Burgunder¹,

Hunziker²

2003

IUBMB Life

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SummaryHereditary spastic paraplegia is a rare disorder with gait disturbance due to a degeneration of the corticospinal tract, sometimes accompanied by involvement of other systems. Out of the 20 loci known so far, eight genes have now been identified, allowing the first molecular and cell studies in the pathophysiology of the disorder. These should also help to understand the function of the corticospinal tract at the molecular level and design strategies to prevent and treat spasticity due to more common causes. The proteins encoded by these genes play a role in development, in signal transduction between axons and myelinating cells, in cellular, particularly axonal trafficking or in energy metabolism. Some of them have actions in several areas of cellular function. Here we review the present knowledge about the genes involved in hereditary spastic paraplegia, a field presently undergoing rapid change.

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Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia

Cited by 314 publications

References 28 publications

Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance

Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance

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

Hereditary Spastic Paraplegia: Clues from a Rare Disorder for a Common Problem?

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