9DMR

Solution NMR structure of the calcium insensitive human LETM1 F-EF-hand domain mutant in the absence of calcium

Summary for 9DMR

• Entry DOI: 10.2210/pdb9dmr/pdb
• NMR Information: BMRB: 31205
• Descriptor: Mitochondrial proton/calcium exchanger protein (1 entity 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: 6694.66

Authors

Lin, Q.T.,Stathopulos, P.B. (deposition date: 2024-09-14, release date: 2025-05-07)

Primary citation

Lin, Q.T.,Colussi, D.M.,Stathopulos, P.B.
The apo LETM1 F-EF-hand adopts a closed conformation that underlies a multi-modal sensory role in mitochondria.
Febs Lett., 599:971-988, 2025

PubMed Abstract: Leucine zipper EF-hand containing transmembrane protein-1 (LETM1) plays a critical role in mitochondrial function, with haploinsufficiency linked to Wolf-Hirschhorn syndrome. Here, we present the solution NMR structure of the calcium (Ca)-depleted LETM1 EF-hand domain, revealing a closed conformation facilitated by a distinct F-helix pivot rather than decreased interhelical angle. Further, we observe regiospecific unfolding in response to hot and cold denaturation and show H662 has a pKa in-line with physiological pH fluctuations. Finally, we demonstrate Ca-dependent transient interactions between the EF-hand and other LETM1 or GHITM protein domains. Collectively, our data reveal the apo-to-holo structural dynamics and mechanisms underlying the multi-modal sensing by the LETM1 EF-hand domain, highlighting its role as an adaptable regulatory element within the mitochondrial matrix.

PubMed: 39927520
DOI: 10.1002/1873-3468.70006

Experimental method

SOLUTION NMR