PMID- 29483649
OWN - NLM
STAT- MEDLINE
DCOM- 20190722
LR  - 20190722
IS  - 1545-9985 (Electronic)
IS  - 1545-9985 (Linking)
VI  - 25
IP  - 3
DP  - 2018 Mar
TI  - Structural basis for GTP hydrolysis and conformational change of MFN1 in 
      mediating membrane fusion.
PG  - 233-243
LID - 10.1038/s41594-018-0034-8 [doi]
AB  - Fusion of the outer mitochondrial membrane is mediated by the dynamin-like GTPase 
      mitofusin (MFN). Here, we determined the structure of the minimal GTPase domain 
      (MGD) of human MFN1 in complex with GDP-BeF(3)(-). The MGD folds into a canonical 
      GTPase fold with an associating four-helix bundle, HB1, and forms a dimer. A 
      potassium ion in the catalytic core engages GDP and BeF(3)(-) (GDP-BeF(3)(-)). 
      Enzymatic analysis has confirmed that efficient GTP hydrolysis by MFN1 requires 
      potassium. Compared to previously reported MGD structures, the HB1 structure 
      undergoes a major conformational change relative to the GTPase domains, as they 
      move from pointing in opposite directions to point in the same direction, 
      suggesting that a swing of the four-helix bundle can pull tethered membranes 
      closer to achieve fusion. The proposed model is supported by results from in 
      vitro biochemical assays and mitochondria morphology rescue assays in 
      MFN1-deleted cells. These findings offer an explanation for how 
      Charcot-Marie-Tooth neuropathy type 2 A (CMT2A)-causing mutations compromise 
      MFN-mediated fusion.
FAU - Yan, Liming
AU  - Yan L
AD  - School of Medicine, Tsinghua University, Beijing, China.
FAU - Qi, Yuanbo
AU  - Qi Y
AUID- ORCID: 0000-0002-6589-3677
AD  - Department of Genetics and Cell Biology, College of Life Sciences, Nankai 
      University, and Tianjin Key Laboratory of Protein Sciences, Tianjin, China.
FAU - Huang, Xiaofang
AU  - Huang X
AD  - Department of Genetics and Cell Biology, College of Life Sciences, Nankai 
      University, and Tianjin Key Laboratory of Protein Sciences, Tianjin, China.
FAU - Yu, Caiting
AU  - Yu C
AD  - School of Medicine, Tsinghua University, Beijing, China.
FAU - Lan, Lan
AU  - Lan L
AD  - National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy 
      of Science, Beijing, China.
FAU - Guo, Xiangyang
AU  - Guo X
AD  - Department of Genetics and Cell Biology, College of Life Sciences, Nankai 
      University, and Tianjin Key Laboratory of Protein Sciences, Tianjin, China.
FAU - Rao, Zihe
AU  - Rao Z
AD  - School of Medicine, Tsinghua University, Beijing, China.
AD  - National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy 
      of Science, Beijing, China.
FAU - Hu, Junjie
AU  - Hu J
AUID- ORCID: 0000-0003-4712-2243
AD  - National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy 
      of Science, Beijing, China. huj@ibp.ac.cn.
FAU - Lou, Zhiyong
AU  - Lou Z
AD  - School of Medicine, Tsinghua University, Beijing, China. 
      louzy@mail.tsinghua.edu.cn.
AD  - Collaborative Innovation Center for Biotherapy, Tsinghua University, Tsinghua, 
      China. louzy@mail.tsinghua.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180226
PL  - United States
TA  - Nat Struct Mol Biol
JT  - Nature structural & molecular biology
JID - 101186374
RN  - 0 (Mitochondrial Membrane Transport Proteins)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.5.- (Mfn1 protein, human)
SB  - IM
MH  - GTP Phosphohydrolases/*chemistry/genetics/metabolism
MH  - Guanosine Triphosphate/*chemistry/metabolism
MH  - Humans
MH  - Hydrolysis
MH  - Membrane Fusion
MH  - Mitochondrial Membrane Transport Proteins/*chemistry/genetics/metabolism
MH  - Models, Molecular
MH  - Mutation
MH  - Protein Conformation
MH  - Protein Domains
MH  - Protein Multimerization
EDAT- 2018/02/28 06:00
MHDA- 2019/07/23 06:00
CRDT- 2018/02/28 06:00
PHST- 2017/09/12 00:00 [received]
PHST- 2018/01/24 00:00 [accepted]
PHST- 2018/02/28 06:00 [pubmed]
PHST- 2019/07/23 06:00 [medline]
PHST- 2018/02/28 06:00 [entrez]
AID - 10.1038/s41594-018-0034-8 [pii]
AID - 10.1038/s41594-018-0034-8 [doi]
PST - ppublish
SO  - Nat Struct Mol Biol. 2018 Mar;25(3):233-243. doi: 10.1038/s41594-018-0034-8. Epub 
      2018 Feb 26.