An AI-informed NMR structure reveals an extraordinary LETM1 F-EF-hand domain that functions as a two-way regulator of mitochondrial calcium.
Structure
; 2024 Sep 17.
Article
em En
| MEDLINE
| ID: mdl-39317198
ABSTRACT
AlphaFold can accurately predict static protein structures but does not account for solvent conditions. Human leucine zipper EF-hand transmembrane protein-1 (LETM1) has one sequence-identifiable EF-hand but how calcium (Ca2+) affects structure and function remains enigmatic. Here, we used highly confident AlphaFold Cα predictions to guide nuclear Overhauser effect (NOE) assignments and structure calculation of the LETM1 EF-hand in the presence of Ca2+. The resultant NMR structure exposes pairing between a partial loop-helix and full helix-loop-helix, forming an unprecedented F-EF-hand with non-canonical Ca2+ coordination but enhanced hydrophobicity for protein interactions compared to calmodulin. The structure also reveals the basis for pH sensing at the link between canonical and partial EF-hands. Functionally, mutations that augmented or weakened Ca2+ binding increased or decreased matrix Ca2+, respectively, establishing F-EF as a two-way mitochondrial Ca2+ regulator. Thus, we show how to synergize AI prediction with NMR data, elucidating a solution-specific and extraordinary LETM1 F-EF-hand.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Structure
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Canadá
País de publicação:
Estados Unidos