6agh

From Proteopedia

Crystal structure of EFHA1 in Apo-State

PDB ID 6agh

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Structural highlights

6agh is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.742Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MICU2_HUMAN Key regulator of mitochondrial calcium uniporter (MCU) required to limit calcium uptake by MCU when cytoplasmic calcium is low (PubMed:24503055, PubMed:24560927, PubMed:26903221). MICU1 and MICU2 form a disulfide-linked heterodimer that stimulate and inhibit MCU activity, depending on the concentration of calcium (PubMed:24560927). MICU2 acts as a gatekeeper of MCU that senses calcium level via its EF-hand domains: prevents channel opening at resting calcium, avoiding energy dissipation and cell-death triggering (PubMed:24560927).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

The mitochondrial Ca(2+) uniporter complex (MCUC) is responsible for Ca(2+) influx into the mitochondrial matrix, playing critical roles in various mitochondrial functions. Eukaryotic MCUC consists of multiple subunits, and its Ca(2+) influx activity is controlled by regulatory subunits, including mitochondrial Ca(2+) uptake 1 (MICU1) and its paralogs (MICU2 and MICU3). However, the underlying mechanism remains unclear. Here, we determined multiple crystal structures of MICU2 and MICU3 from Homo sapiens. Our data demonstrate that distinct MICU protein N-domains determine the specific type of MICU dimers that perform the opposing roles in mitochondrial Ca(2+) uptake at low cytosolic Ca(2+) levels. In contrast, at high cytosolic Ca(2+) levels, all MICU proteins undergo dimer rearrangement induced by Ca(2+) binding, which releases the suppression of the MCUC pore-forming subunit and promotes the influx of large amounts of Ca(2+). Altogether, our results elucidate the delicate mechanism of mitochondrial Ca(2+) uptake regulation by MICU proteins.

Dimerization of MICU Proteins Controls Ca(2+) Influx through the Mitochondrial Ca(2+) Uniporter.,Xing Y, Wang M, Wang J, Nie Z, Wu G, Yang X, Shen Y Cell Rep. 2019 Jan 29;26(5):1203-1212.e4. doi: 10.1016/j.celrep.2019.01.022. PMID:30699349^[5]

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

References

↑ Kamer KJ, Mootha VK. MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Rep. 2014 Mar;15(3):299-307. doi: 10.1002/embr.201337946. Epub 2014 Feb 6. PMID:24503055 doi:http://dx.doi.org/10.1002/embr.201337946
↑ Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabo I, De Stefani D, Rizzuto R. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell. 2014 Mar 6;53(5):726-37. doi: 10.1016/j.molcel.2014.01.013. Epub 2014, Feb 20. PMID:24560927 doi:http://dx.doi.org/10.1016/j.molcel.2014.01.013
↑ Petrungaro C, Zimmermann KM, Kuttner V, Fischer M, Dengjel J, Bogeski I, Riemer J. The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake. Cell Metab. 2015 Oct 6;22(4):721-33. doi: 10.1016/j.cmet.2015.08.019. Epub 2015, Sep 17. PMID:26387864 doi:http://dx.doi.org/10.1016/j.cmet.2015.08.019
↑ Matesanz-Isabel J, Arias-del-Val J, Alvarez-Illera P, Fonteriz RI, Montero M, Alvarez J. Functional roles of MICU1 and MICU2 in mitochondrial Ca(2+) uptake. Biochim Biophys Acta. 2016 Jun;1858(6):1110-7. doi: 10.1016/j.bbamem.2016.02.022., Epub 2016 Feb 18. PMID:26903221 doi:http://dx.doi.org/10.1016/j.bbamem.2016.02.022
↑ Xing Y, Wang M, Wang J, Nie Z, Wu G, Yang X, Shen Y. Dimerization of MICU Proteins Controls Ca(2+) Influx through the Mitochondrial Ca(2+) Uniporter. Cell Rep. 2019 Jan 29;26(5):1203-1212.e4. doi: 10.1016/j.celrep.2019.01.022. PMID:30699349 doi:http://dx.doi.org/10.1016/j.celrep.2019.01.022