Structures of human mitofusin 1 provide insight into mitochondrial tethering

Qi, Yuming; Yan, Liming; Yu, Chengbin; Guo, Xiangyang; Zhou, Xin; Hu, Xiaoyu; Huang, Xiaofang; Rao, Zihe; Lou, Zhiyong; Hu, Junjie

doi:10.1083/jcb.201609019

Cited by 149 publications

(188 citation statements)

References 36 publications

(52 reference statements)

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“…However, membrane fusion may require the aid of other proteins, which was not possible to elucidate with our experimental setup. Nevertheless, the observation of tethering underlines the functional similarity of GBPs with atlastins and also other dynamin family members as recently shown for mitofusin (53). Recent studies on the antibacterial effect of GBPs indicate that hGBP1 and 2 are recruited to bacterial inclusions of Chlamydia trachomatis and trigger their rerouting for lysosomal degradation (54).…”

Section: Discussionmentioning

confidence: 99%

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

Shydlovskyi

Zienert

İnce

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

120

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Dynamin-like proteins (DLPs) mediate various membrane fusion and fission processes within the cell, which often require the polymerization of DLPs. An IFN-inducible family of DLPs, the guanylate-binding proteins (GBPs), is involved in antimicrobial and antiviral responses within the cell. Human guanylate-binding protein 1 (hGBP1), the founding member of GBPs, is also engaged in the regulation of cell adhesion and migration. Here, we show how the GTPase cycle of farnesylated hGBP1 (hGBP1F) regulates its self-assembly and membrane interaction. Using vesicles of various sizes as a lipid bilayer model, we show GTP-dependent membrane binding of hGBP1F. In addition, we demonstrate nucleotide-dependent tethering ability of hGBP1F. Furthermore, we report nucleotide-dependent polymerization of hGBP1F, which competes with membrane binding of the protein. Our results show that hGBP1F acts as a nucleotide-controlled molecular switch by modulating the accessibility of its farnesyl moiety, which does not require any supportive proteins.

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Section: Discussionmentioning

confidence: 99%

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

Shydlovskyi

Zienert

İnce

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

120

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“…Recently, two independent studies have shed novel insights into Mfn structure and mitochondrial tethering (Qi et al, 2016;Cao et al, 2017). Crystal structures were generated from Mfn1 constructs containing an internal deletion of the second helical bundle and predicted transmembrane (TM) regions (Qi et al, 2016;Cao et al, 2017). The proposed model for fusion involves rotation of HB1 (helix bundle 1 extending from the GTPase domain) upon GTP hydrolysis, which allows HB2 (helix bindle 2 extending from the C terminal) to bend and attach to the GTPase domain, thereby bringing opposing mitochondrial membranes together (Qi et al, 2016).…”

Section: Genomic and Protein Organization Of The Mitofusinsmentioning

confidence: 99%

“…Outer membrane fusion is mediated by the mitofusins, large GTPases that traverse the outer mitochondrial membrane twice, with the amino and carboxy termini both facing into the cytoplasm (Alexander et al, 2000). Mitofusins form both homo-oligomeric (Mfn1-Mfn1 or Mfn2-Mfn2) and hetero-oligomeric (Mfn1-Mfn2) complexes in trans between apposing mitochondria (Chen et al, 2003;Griffin & Chan, 2006;Qi et al, 2016). Prior to fusion, curving of the outer membranes is promoted by the hydrolysis of cardiolipin to phosphatidic acid, a process mediated by phospholipase-D .…”

Section: Mitochondrial Dynamics (1) Mitochondrial Fusionmentioning

confidence: 99%

“…2B) (Chen et al, 2003;Koshiba et al, 2004). Recently, two independent studies have shed novel insights into Mfn structure and mitochondrial tethering (Qi et al, 2016;Cao et al, 2017). Crystal structures were generated from Mfn1 constructs containing an internal deletion of the second helical bundle and predicted transmembrane (TM) regions (Qi et al, 2016;Cao et al, 2017).…”

Section: Genomic and Protein Organization Of The Mitofusinsmentioning

confidence: 99%

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Structure, function, and regulation of mitofusin‐2 in health and disease

2017

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Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non-neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.

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“…An interconnected and fused network sustains oxidative phosphorylation (OXPHOS), ATP production, and the mixing of mitochondrial DNA (mtDNA), whilst a partial mitochondria fragmentation tends to isolate damaged portions, thus limiting the stress eventually deriving from a prolonged organelle damage. Fusion of the outer mitochondrial membranes (OMMs) depends mainly on the activity of GTPase Mitofusin proteins (Mfn-1 and -2) [2][3][4]. These proteins have broad overlapping roles and are expressed in different tissues, with pleiotropic functions.…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial dynamics in cancer and immune-surveillance

Simula

Nazio

Campello

2017

Seminars in Cancer Biology

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A B S T R A C TMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence.

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Structures of human mitofusin 1 provide insight into mitochondrial tethering

Abstract: Mitofusin 1 (MFN1) mediates mitochondrial fusion, but the mechanisms involved are unclear. Qi et al. present the crystal structures of a minimal GTPase domain of human MFN1, which suggest that MFN1 tethers apposing membranes through nucleotide-dependent dimerization.

Cited by 149 publications

References 36 publications

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

Structure, function, and regulation of mitofusin‐2 in health and disease

The mitochondrial dynamics in cancer and immune-surveillance

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