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Structural and functional analysis of the ASM p.Ala359Asp mutant that causes acid sphingomyelinase deficiency

Authordc.contributor.authorAcuña, Mariana 
Authordc.contributor.authorCastro Fernández, Víctor 
Authordc.contributor.authorLatorre Mora, Mauricio 
Authordc.contributor.authorCastro, Juan 
Authordc.contributor.authorSchuchman, Edward H. 
Authordc.contributor.authorGuixé Leguía, Victoria Cristina 
Authordc.contributor.authorGonzález Canales, Mauricio 
Authordc.contributor.authorZanlungo, Silvana 
Cita de ítemdc.identifier.citationBiochemical and Biophysical Research Communications 479 (2016) 496-501es_ES
Abstractdc.description.abstractNiemann-Pick disease (NPD) type A and B are recessive hereditary disorders caused by deficiency in acid sphingomyelinase (ASM). The p.A1a359Asp mutation has been described in several patients but its functional and structural effects in the protein are unknown. In order to characterize this mutation, we modeled the three-dimensional ASM structure using the recent available crystal of the mammalian ASM as a template. We found that the p.A1a359Asp mutation is localized in the hydrophobic core and far from the sphingomyelin binding site. However, energy function calculations using statistical potentials indicate that the mutation causes a decrease in ASM stability. Therefore, we investigated the functional effect of the p.A1a359Asp mutation in ASM expression, secretion, localization and activity in human fibroblasts. We found a 3.8% residual ASM activity compared to the wild-type enzyme, without changes in the other parameters evaluated. These results support the hypothesis that the p.A1a359Asp mutation causes structural alterations in the hydrophobic environment where ASM is located, decreasing its enzymatic activity. A similar effect was observed in other previously described NPDB mutations located outside the active site of the enzyme. This work shows the first full size ASM mutant model describe at date, providing a complete analysis of the structural and functional effects of the p.A1a359Asp mutation over the stability and activity of the enzyme.es_ES
Patrocinadordc.description.sponsorshipFondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) 1150816 1150460 11150679 Fondo Nacional de Desarrollo de Areas Prioritarias, FONDAP Center for Genome Regulation (CGR) 15090007 Genzyme grant "Assessment of the acid sphingomyelinase gene mutation frequency in the Chilean population" A359D Comision Nacional de Ciencia y Tecnologia (CONICYT) PhD student grant 21120490 FONDECYT Postdoctorado 3160332 National Institutes of Health HD28607es_ES
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile*
Link to Licensedc.rights.uri*
Sourcedc.sourceBiochemical and Biophysical Research Communicationses_ES
Keywordsdc.subjectNiemann-pick diseasees_ES
Keywordsdc.subjectAcid sphingomylienasees_ES
Keywordsdc.subjectSMPD1 mutationses_ES
Títulodc.titleStructural and functional analysis of the ASM p.Ala359Asp mutant that causes acid sphingomyelinase deficiencyes_ES
Document typedc.typeArtículo de revistaes_ES
Indexationuchile.indexArtículo de publicación ISIes_ES

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Attribution-NonCommercial-NoDerivs 3.0 Chile
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile