Language:

The structure of the MICU1‐MICU2 complex unveils the regulation of the mitochondrial calcium uniporter

The EMBO journal, 2020-10, Vol.39 (19), p.e104285-n/a [Peer Reviewed Journal]

2020 The Authors ;2020 The Authors. ;2020 EMBO ;ISSN: 0261-4189 ;EISSN: 1460-2075 ;DOI: 10.15252/embj.2019104285 ;PMID: 32790952

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
The structure of the MICU1‐MICU2 complex unveils the regulation of the mitochondrial calcium uniporter
Author: Wu, Wenping ; Shen, Qingya ; Zhang, Ruiling ; Qiu, Zhiyu ; Wang, Youjun ; Zheng, Jimin ; Jia, Zongchao
Subjects: Accumulation ; Activation ; Binding ; Calcium ; Calcium (mitochondrial) ; Calcium - chemistry ; Calcium - metabolism ; Calcium Channels - chemistry ; Calcium Channels - genetics ; Calcium Channels - metabolism ; Calcium homeostasis ; Calcium influx ; Calcium ions ; Calcium signalling ; Calcium-Binding Proteins - chemistry ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Cation Transport Proteins - chemistry ; Cation Transport Proteins - genetics ; Cation Transport Proteins - metabolism ; Channel gating ; Competition ; Crystal structure ; Crystallography, X-Ray ; EMRE ; Grooves ; Homeostasis ; Humans ; Hydrophobicity ; Interfaces ; Ion Transport ; MICU1‐MICU2 ; Mitochondria ; Mitochondrial Membrane Transport Proteins - chemistry ; Mitochondrial Membrane Transport Proteins - genetics ; Mitochondrial Membrane Transport Proteins - metabolism ; Multiprotein Complexes - chemistry ; Multiprotein Complexes - genetics ; Multiprotein Complexes - metabolism ; Peptides ; Regulation ; Regulatory subunits ; Structural analysis ; Structure-function relationships ; uniporter
Is Part Of: The EMBO journal, 2020-10, Vol.39 (19), p.e104285-n/a
Description: The MICU1‐MICU2 heterodimer regulates the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake. Herein, we present two crystal structures of the MICU1‐MICU2 heterodimer, in which Ca2+‐free and Ca2+‐bound EF‐hands are observed in both proteins, revealing both electrostatic and hydrophobic interfaces. Furthermore, we show that MICU1 interacts with EMRE, another regulator of MCU, through a Ca2+‐dependent alkaline groove. Ca2+ binding strengthens the MICU1‐EMRE interaction, which in turn facilitates Ca2+ uptake. Conversely, the MICU1‐MCU interaction is favored in the absence of Ca2+, thus inhibiting the channel activity. This Ca2+‐dependent switch illuminates how calcium signals are transmitted from regulatory subunits to the calcium channel and the transition between gatekeeping and activation channel functions. Furthermore, competition with an EMRE peptide alters the uniporter threshold in resting conditions and elevates Ca2+ accumulation in stimulated mitochondria, confirming the gatekeeper role of the MICU1‐MICU2 heterodimer. Taken together, these structural and functional data provide new insights into the regulation of mitochondrial calcium uptake. Synopsis The mitochondrial calcium uniporter (MCU) modulating calcium uptake and homeostasis in mitochondria is controlled by the regulatory subunits MICU1 and MICU2. Structural analysis of Ca2+‐free and partial Ca2+‐bound MICU1–MICU2 heterodimers reveals how calcium binding modulates gatekeeping and activation functions of the regulatory subunits. Electrostatic and hydrophobic interfaces are present in Ca2+‐free and Ca2+‐bound MICU1–MICU2 heterodimers, respectively. MICU1 interacts with the poly‐aspartate tail of another regulator, EMRE, via its Ca2+‐dependent alkaline groove Ca2+ allows EMRE to outcompete MCU for MICU1 binding, transforming MICU1–MICU2 from a gatekeeper to an activator of MCU. Competition with an EMRE peptide reduces the threshold of uniporter Ca2+ uptake in resting conditions and increases Ca2+ accumulation in mitochondria upon stimulation. Structural analysis of MICU1–MICU2 heterodimers reveals how Ca2+ binding modulates gatekeeping and activation of the mitochondrial calcium uniporter.
Publisher: England: Blackwell Publishing Ltd
Language: English
Identifier: ISSN: 0261-4189
EISSN: 1460-2075
DOI: 10.15252/embj.2019104285
PMID: 32790952
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
PubMed Central
Alma/SFX Local Collection

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

The structure of the MICU1‐MICU2 complex unveils the regulation of the mitochondrial calcium uniporter

2020 The Authors ;2020 The Authors. ;2020 EMBO ;ISSN: 0261-4189 ;EISSN: 1460-2075 ;DOI: 10.15252/embj.2019104285 ;PMID: 32790952

Searching Remote Databases, Please Wait