9BA1

Solution NMR structure of the human LETM1 F-EF-hand domain in the presence of calcium

Summary for 9BA1

• Entry DOI: 10.2210/pdb9ba1/pdb
• NMR Information: BMRB: 31155
• Descriptor: Mitochondrial proton/calcium exchanger protein, CALCIUM ION (2 entities in total)
• Functional Keywords: ef-hand, f-ef-hand, letm1, mitochondrial, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 6821.77

Authors

Lin, Q.T.,Stathopulos, P.B. (deposition date: 2024-04-03, release date: 2024-10-16, Last modification date: 2024-11-27)

Primary citation

Lin, Q.T.,Colussi, D.M.,Lake, T.,Stathopulos, P.B.
An AI-informed NMR structure reveals an extraordinary LETM1 F-EF-hand domain that functions as a two-way regulator of mitochondrial calcium.
Structure, 32:2063-, 2024

PubMed 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 (Ca) 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 Ca. 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 Ca 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 Ca binding increased or decreased matrix Ca, respectively, establishing F-EF as a two-way mitochondrial Ca regulator. Thus, we show how to synergize AI prediction with NMR data, elucidating a solution-specific and extraordinary LETM1 F-EF-hand.

PubMed: 39317198
DOI: 10.1016/j.str.2024.08.020

Experimental method

SOLUTION NMR