ParkinsonCanadaV1, Main, Exploration, bibRecord, 001591

Structural Basis of Defects in the Sacsin HEPN Domain Responsible for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)*

Identifieur interne : 001591 ( Main/Exploration ); précédent : 001590; suivant : 001592

Structural Basis of Defects in the Sacsin HEPN Domain Responsible for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)*

Auteurs : Guennadi Kozlov ; Alexey Y. Denisov ; Martine Girard ; Marie-Josée Dicaire ; Jason Hamlin ; Peter S. Mcpherson ; Bernard Brais ; Kalle Gehring

Source :

The Journal of Biological Chemistry [ 0021-9258 ] ; 2011.

RBID : PMC:3121481

Abstract

Sacsin is a 520-kDa protein mutated in the early-onset neurodevelopmental and neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The C terminus of the protein contains an HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain of unknown function. Here, we determined the high-resolution 1.9-Å crystal structure of the HEPN domain from human sacsin. The structure is composed of five parallel α-helices with a large loop of several short helical segments. Two HEPN protomers assemble as a dimer to form a large positively charged cavity at the dimer interface that binds GTP and other nucleotides. The crystal structure reveals that the ARSACS N4549D mutation disrupts dimerization and protein folding. This study provides novel insights into the oligomerization state of sacsin and functions that are lost in mutations that cause ARSACS.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121481

DOI: 10.1074/jbc.M111.232884
PubMed: 21507954
PubMed Central: 3121481

Affiliations:

Le document en format XML

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<front><div type="abstract" xml:lang="en"><p>Sacsin is a 520-kDa protein mutated in the early-onset neurodevelopmental and neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The C terminus of the protein contains an HEPN (<underline>h</underline>
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ukaryotes and <underline>p</underline>
rokaryotes <underline>n</underline>
ucleotide-binding) domain of unknown function. Here, we determined the high-resolution 1.9-Å crystal structure of the HEPN domain from human sacsin. The structure is composed of five parallel α-helices with a large loop of several short helical segments. Two HEPN protomers assemble as a dimer to form a large positively charged cavity at the dimer interface that binds GTP and other nucleotides. The crystal structure reveals that the ARSACS N4549D mutation disrupts dimerization and protein folding. This study provides novel insights into the oligomerization state of sacsin and functions that are lost in mutations that cause ARSACS.</p>
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La maladie de Parkinson au Canada (serveur d'exploration)

Structural Basis of Defects in the Sacsin HEPN Domain Responsible for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)*

Structural Basis of Defects in the Sacsin HEPN Domain Responsible for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)*

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Abstract

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