Titre :

New insights into the pathogenicity of TMEM165 variants using structural modeling based on AlphaFold 2 predictions

Auteur(s) :

Legrand, Dominique [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Herbaut, Melissandre [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Durin, Zoe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Brysbaert, Guillaume [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Bardor, Muriel [Auteur]
Laboratoire de Glycobiologie et Matrice Extracellulaire Végétale [Glyco-MEV]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Lensink, Marc [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Foulquier, Francois [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Titre de la revue :

Computational and Structural Biotechnology Journal

Nom court de la revue :

Computational and Structural Biotechnology Journal

Numéro :

21

Pagination :

3424-3436

Éditeur :

Elsevier BV

Date de publication :

2023-06-17

ISSN :

2001-0370

Mot(s)-clé(s) en anglais :

TMEM165
CDG
Glycosylation
Manganese
Modeling

Discipline(s) HAL :

Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique

Résumé en anglais : [en]

TMEM165 is a Golgi protein playing a crucial role in Mn2+ transport, and whose mutations in patients are known to cause Congenital Disorders of Glycosylation. Some of those mutations affect the highly-conserved consensus ...
Lire la suite >TMEM165 is a Golgi protein playing a crucial role in Mn2+ transport, and whose mutations in patients are known to cause Congenital Disorders of Glycosylation. Some of those mutations affect the highly-conserved consensus motifs E-φ-G-D-[KR]-[TS] characterizing the CaCA2/UPF0016 family, presumably important for the transport of Mn2+ which is essential for the function of many Golgi glycosylation enzymes. Others, 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, AlphaFold 2 was used to build a TMEM165 model that was then refined by molecular dynamics simulation with membrane lipids and water. This model provides a realistic picture of the 3D protein scaffold formed from a two-fold repeat of three transmembrane helices/domains 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 vitro, 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 provide great confidence in the predicted TMEM165 model whose structural features are discussed in the study and compared to other structural and functional TMEM165 homologs from the CaCA2/UPF0016 family and the LysE superfamily.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Projet ANR :

Exploration des roles de TMEM165 et SPCA1 dans l'homéostasie Golgienne du Ca2+ et du Mn2+, la glycosylation golgienne et la sécrétion des protéines, application aux pathologies TMEM165-CDG et HHD.
Glyco-ingénierie des diatomées pour la production des biomédicaments

Établissement(s) :

Université de Lille
CNRS

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Équipe(s) de recherche :

Mécanismes moléculaires de la N-glycosylation et pathologies associées
Computational Molecular Systems Biology

Date de dépôt :

2023-07-19T08:00:30Z
2023-08-31T16:23:17Z