Journal
GLYCOCONJUGATE JOURNAL
Volume 33, Issue 2, Pages 237-244Publisher
SPRINGER
DOI: 10.1007/s10719-016-9661-7
Keywords
Enzyme; Gaucher disease; Glycan; Lysosome; Molecular dynamics
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Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq - MCT) [DCR-0037-1.06/13]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES - MEC)
- Fundacao de Amparo a Pesquisa do Rio Grande do Sul (FAPERGS)
- Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco (FACEPE) [APQ-0398-1.06/13]
- Fundo de Incentivo a Pesquisa e Eventos do Hospital de Clinicas de Porto Alegre (FIPE-HCPA)
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Gaucher disease, an autosomal recessive disorder, is caused by a deficiency of glucocerebrosidase (GCase) enzyme, a peripheral membrane-associated glycoprotein that hydrolyses glucosylceramide in lysosomes. Glycosylation is essential for the development of a catalytically active enzyme, specifically in the first site, located at Asn19. However, both the molecular basis of the relevance of N-glycosylation over GCase activity and the effects of glycosylation over its structure and dynamics are still not fully understood. Thus, the present work evaluated GCase enzyme in increasing glycosylation content using triplicate unbiased molecular dynamics simulations. Accordingly, the N-linked glycan chains caused local conformational stabilization effects over the protein, as well as in regions flanking the enzyme catalytic dyad. In the case of the Asn19-linked glycan, it also occurred around region 438-444, where one of the most prevalent GCase mutations is found. Markedly, an increasing catalytic dyad organization was related to increasing glycosylation contents, offering the first atomic-level explanation for the experimental observation that GCase activity is controlled by glycosylation, especially at Asn19.
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