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9dmr

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

Structural highlights

9dmr is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 10 models
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LETM1_HUMAN Wolf-Hirschhorn syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

LETM1_HUMAN Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport (PubMed:18628306, PubMed:19797662, PubMed:24344246, PubMed:24898248, PubMed:29123128, PubMed:32139798, PubMed:36055214, PubMed:36321428). Mediates proton-dependent calcium efflux from mitochondrion (PubMed:19797662, PubMed:24344246, PubMed:29123128). Functions also as an electroneutral mitochondrial proton/potassium exchanger (PubMed:24898248, PubMed:36055214, PubMed:36321428). Crucial for the maintenance of mitochondrial tubular networks and for the assembly of the supercomplexes of the respiratory chain (PubMed:18628306, PubMed:36055214). Required for the maintenance of the tubular shape and cristae organization (PubMed:18628306, PubMed:32139798).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

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(2+))-depleted LETM1 EF-hand domain, revealing a closed conformation facilitated by a distinct F(1)-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(2+)-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.

The apo LETM1 F-EF-hand adopts a closed conformation that underlies a multi-modal sensory role in mitochondria.,Lin QT, Colussi DM, Stathopulos PB FEBS Lett. 2025 Apr;599(7):971-988. doi: 10.1002/1873-3468.70006. Epub 2025 Feb , 10. PMID:39927520^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tamai S, Iida H, Yokota S, Sayano T, Kiguchiya S, Ishihara N, Hayashi J, Mihara K, Oka T. Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L. J Cell Sci. 2008 Aug 1;121(Pt 15):2588-600. PMID:18628306 doi:10.1242/jcs.026625
↑ Jiang D, Zhao L, Clapham DE. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science. 2009 Oct 2;326(5949):144-7. PMID:19797662 doi:10.1126/science.1175145
↑ Tsai MF, Jiang D, Zhao L, Clapham D, Miller C. Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1. J Gen Physiol. 2014 Jan;143(1):67-73. PMID:24344246 doi:10.1085/jgp.201311096
↑ De Marchi U, Santo-Domingo J, Castelbou C, Sekler I, Wiederkehr A, Demaurex N. NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state. J Biol Chem. 2014 Jul 18;289(29):20377-85. PMID:24898248 doi:10.1074/jbc.M113.540898
↑ Huang E, Qu D, Huang T, Rizzi N, Boonying W, Krolak D, Ciana P, Woulfe J, Klein C, Slack RS, Figeys D, Park DS. PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress. Nat Commun. 2017 Nov 9;8(1):1399. PMID:29123128 doi:10.1038/s41467-017-01435-1
↑ Nakamura S, Matsui A, Akabane S, Tamura Y, Hatano A, Miyano Y, Omote H, Kajikawa M, Maenaka K, Moriyama Y, Endo T, Oka T. The mitochondrial inner membrane protein LETM1 modulates cristae organization through its LETM domain. Commun Biol. 2020 Mar 5;3(1):99. PMID:32139798 doi:10.1038/s42003-020-0832-5
↑ Kaiyrzhanov R, Mohammed SEM, Maroofian R, Husain RA, Catania A, Torraco A, Alahmad A, Dutra-Clarke M, Grønborg S, Sudarsanam A, Vogt J, Arrigoni F, Baptista J, Haider S, Feichtinger RG, Bernardi P, Zulian A, Gusic M, Efthymiou S, Bai R, Bibi F, Horga A, Martinez-Agosto JA, Lam A, Manole A, Rodriguez DP, Durigon R, Pyle A, Albash B, Dionisi-Vici C, Murphy D, Martinelli D, Bugiardini E, Allis K, Lamperti C, Reipert S, Risom L, Laugwitz L, Di Nottia M, McFarland R, Vilarinho L, Hanna M, Prokisch H, Mayr JA, Bertini ES, Ghezzi D, Østergaard E, Wortmann SB, Carrozzo R, Haack TB, Taylor RW, Spinazzola A, Nowikovsky K, Houlden H. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement. Am J Hum Genet. 2022 Sep 1;109(9):1692-1712. PMID:36055214 doi:10.1016/j.ajhg.2022.07.007
↑ Austin S, Mekis R, Mohammed SEM, Scalise M, Wang WA, Galluccio M, Pfeiffer C, Borovec T, Parapatics K, Vitko D, Dinhopl N, Demaurex N, Bennett KL, Indiveri C, Nowikovsky K. TMBIM5 is the Ca(2+) /H(+) antiporter of mammalian mitochondria. EMBO Rep. 2022 Dec 6;23(12):e54978. PMID:36321428 doi:10.15252/embr.202254978
↑ Lin QT, Colussi DM, Stathopulos PB. The apo LETM1 F-EF-hand adopts a closed conformation that underlies a multi-modal sensory role in mitochondria. FEBS Lett. 2025 Apr;599(7):971-988. PMID:39927520 doi:10.1002/1873-3468.70006