| Structural highlights
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
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(2+)) affects structure and function remains enigmatic. Here, we used highly confident AlphaFold Calpha predictions to guide nuclear Overhauser effect (NOE) assignments and structure calculation of the LETM1 EF-hand in the presence of Ca(2+). 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(2+) 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(2+) binding increased or decreased matrix Ca(2+), respectively, establishing F-EF as a two-way mitochondrial Ca(2+) regulator. Thus, we show how to synergize AI prediction with NMR data, elucidating a solution-specific and extraordinary LETM1 F-EF-hand.
An AI-informed NMR structure reveals an extraordinary LETM1 F-EF-hand domain that functions as a two-way regulator of mitochondrial calcium.,Lin QT, Colussi DM, Lake T, Stathopulos PB Structure. 2024 Sep 17:S0969-2126(24)00363-0. doi: 10.1016/j.str.2024.08.020. PMID:39317198[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, Lake T, Stathopulos PB. 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:S0969-2126(24)00363-0. PMID:39317198 doi:10.1016/j.str.2024.08.020
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