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Article Dans Une Revue FEBS Open Bio Année : 2023

Solving the pathogenecity of TMEM16 variants using structural modeling based on AlphaFold 2 predictions

Résumé

TMEM165 is a protein playing a crucial role in Mn2+ transport in the Golgi, and whose mutations in patients are known to cause congenital disorders of glycosylation (CDG). Whereas some of those mutations affect either the expression or the localization of TMEM165, others clearly impair the Mn2+ transport which is essential for the function of many Golgi glycosylation enzymes. The identified mutations either affect the highly-conserved consensus motifs E-φ-G-D-[KR]-[TS] characterizing the UPF00016/CaCA2 family, hence presumably important for the protein function, or, like the G>R304 mutation, are far away from these motifs in the sequence. Until recently, the classical membrane protein topology prediction methods were unable to provide a clear picture of the organization of TMEM165 inside the cell membrane, or to explain in a convincing manner the impact of patient and experimentally-generated mutations on the transporter function of TMEM165. In this study, the abilities of AlphaFold 2 have been used to build a TMEM165 model that was then subjected to molecular dynamics (MD) simulation including membrane lipids and water. This model provides a credible picture of the 3D protein scaffold formed from a twofold repeat of three transmembrane helices/domains (TMD) where the consensus motifs face each other to form a putative acidic cation-binding site at the cytosolic side of the protein. It sheds new light on the impact of mutations on the transporter function of TMEM165, found in patients and studied experimentally in vivo, formerly and within this study. More particularly and very interestingly, this model explains the impact of the G>R304 mutation on TMEM165’s function. These findings give great confidence in the predicted TMEM165 model whose structural features are discussed in the study and compared with other structural and functional homologues of TMEM165.
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Dates et versions

hal-04235441 , version 1 (13-10-2023)

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Dominique Legrand, Mélissandre Herbaut, Zoé Durin, Guillaume Brysbaert, Marc F Lensink, et al.. Solving the pathogenecity of TMEM16 variants using structural modeling based on AlphaFold 2 predictions. FEBS Open Bio, 2023, 13, pp.249. ⟨10.1002/2211-5463.13646⟩. ⟨hal-04235441⟩

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