Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 479, Issue 3, Pages 496-501Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2016.09.096
Keywords
Niemann-pick disease; Acid sphingomylienase; SMPD1 mutations; p.Ala359Asp
Categories
Funding
- Fondo 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 [HD28607]
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Niemann-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. (C) 2016 Elsevier Inc. All rights reserved.
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