O papel da seipina na síndrome de Berardinelli e em diferentes síndromes neurodegenerativas: associação entre mutação, estrutura e função

Abstract

Seipin is a protein located in the membrane of the endoplasmic reticulum, essential for cellular homeostasis. The present work aims to evaluate the impact of pathogenic mutations N88S, S90L, and A212P on seipin structure through in silico studies to determine their effects on the protein conformation. The methodology involved modeling seipin isoforms using tools such as AlphaFold, SWISS-MODEL, and structural data analysis through platforms like Ensembl, UniProt, and GTEx. The pathogenicity of the mutations was analyzed using AlphaMissense, and structural changes were assessed based on geometric simulations and non-covalent interaction analyses. The results indicate that the N88S and A212P mutations are indeed pathogenic, especially since they are located in critical regions of seipin, such as the N88 glycosylation site and the β2 and β8 sheets. Furthermore, all mentioned 4 mutations critically affect seipin structure from a molecular dynamics approximation and are associated with dysfunctions in cellular membrane homeostasis. These structural alterations may contribute to the development of diseases such as congenital lipodystrophy and hereditary neuropathies, highlighting the relevance of these mutations to observed pathogenicity. In summary, the study underscores the complex relationship between seipin genetic variations and pathogenicity, suggesting that isoform- and tissue-specific interventions are necessary. Future studies should focus on the molecular dynamics of mutations to better understand their effects on seipin structure and resulting phenotypes.