The Atlastin C-terminal Tail Is an Amphipathic Helix That Perturbs the Bilayer Structure during Endoplasmic Reticulum Homotypic Fusion

Faust, Joseph E.; Desai, Tanvi; Verma, Avani; Ulengin, Idil; Sun, Tzu-Lin; Moss, Tyler J.; Betancourt-Solis, Miguel A.; Huang, Huey W.; Lee, Tina; McNew, James A.

doi:10.1074/jbc.m114.601823

Cited by 47 publications

(54 citation statements)

References 33 publications

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“…Whereas Drosophila atlastin is an efficient fusogen in vitro (5,(31)(32)(33)(34)(35), the human atlastin proteins have been resistant to in vitro fusion analysis (36). We have confirmed that human atlastin-1 does not significantly promote membrane fusion in vitro (Fig.…”

Section: Biochemical Analysis Of Human Atlastin-1 and Human-drosophilsupporting

confidence: 64%

The atlastin membrane anchor forms an intramembrane hairpin that does not span the phospholipid bilayer

Betancourt-Solis

Desai²,

McNew

2018

Journal of Biological Chemistry

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The endoplasmic reticulum (ER) is composed of flattened sheets and interconnected tubules that extend throughout the cytosol and makes physical contact with all other cytoplasmic organelles. This cytoplasmic distribution requires continuous remodeling. These discrete ER morphologies require specialized proteins that drive and maintain membrane curvature. The GTPase atlastin is required for homotypic fusion of ER tubules. All atlastin homologs possess a conserved domain architecture consisting of a GTPase domain, a three-helix bundle middle domain, a hydrophobic membrane anchor, and a C-terminal cytosolic tail. Here, we examined several Drosophila-human atlastin chimeras to identify functional domains of human atlastin-1 in vitro. Although all chimeras could hydrolyze GTP, only chimeras containing the human C-terminal tail, hydrophobic segments, or both could fuse membranes in vitro. We also determined that co-reconstitution of atlastin with reticulon does not influence GTPase activity or membrane fusion. Finally, we found that both human and Drosophila atlastin hydrophobic membrane anchors do not span the membrane, but rather form two intramembrane hairpin loops. The topology of these hairpins remains static during membrane fusion and does not appear to play an active role in lipid mixing.

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Section: Biochemical Analysis Of Human Atlastin-1 and Human-drosophilsupporting

confidence: 64%

The atlastin membrane anchor forms an intramembrane hairpin that does not span the phospholipid bilayer

Betancourt-Solis

Desai²,

McNew

2018

Journal of Biological Chemistry

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“…In this case, GTP hydrolysis may be required to pull opposing membranes toward each other by catalyzing the transition from the open to the cross‐over helical conformation. Fusion of the closely juxtaposed membranes may then be further facilitated by disturbance of the lipids by TM‐regions and the amphipathic helix in the C‐terminal tail of atlastin . In addition, it has been suggested that the GTPase function may be used to recycle atlastin dimers in the cross‐over conformation back to the open conformation to allow new rounds of tethering across opposing membranes .…”

Section: Harnessing the Energy Of Gtp Hydrolysis For A Mechano‐chemicmentioning

confidence: 99%

Invited review: Mechanisms of GTP hydrolysis and conformational transitions in the dynamin superfamily

2016

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Dynamin superfamily proteins are multidomain mechano‐chemical GTPases which are implicated in nucleotide‐dependent membrane remodeling events. A prominent feature of these proteins is their assembly‐ stimulated mechanism of GTP hydrolysis. The molecular basis for this reaction has been initially clarified for the dynamin‐related guanylate binding protein 1 (GBP1) and involves the transient dimerization of the GTPase domains in a parallel head‐to‐head fashion. A catalytic arginine finger from the phosphate binding (P‐) loop is repositioned toward the nucleotide of the same molecule to stabilize the transition state of GTP hydrolysis. Dynamin uses a related dimerization‐dependent mechanism, but instead of the catalytic arginine, a monovalent cation is involved in catalysis. Still another variation of the GTP hydrolysis mechanism has been revealed for the dynamin‐like Irga6 which bears a glycine at the corresponding position in the P‐loop. Here, we highlight conserved and divergent features of GTP hydrolysis in dynamin superfamily proteins and show how nucleotide binding and hydrolysis are converted into mechano‐chemical movements. We also describe models how the energy of GTP hydrolysis can be harnessed for diverse membrane remodeling events, such as membrane fission or fusion. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 580–593, 2016.

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“…ER membranes are first brought in close proximity by GTP-dependent formation and conformational transition of membrane-bridging Atlastin complexes. ER membranes are then destabilized by a C-terminal amphipathic helix which alters the lipid bilayer integrity [10,56,57]. Interestingly, similar membrane-proximal amphipathic helices, with a potential function in membrane destabilization and fusion, were also found in other fusion proteins such as the synaptic v-SNARE protein VAMP2 and the flavivirus protein E from the dengue virus [54,55,59], suggesting that amphipathic helices are a force to be reckoned with in membrane fusion events.…”

Section: Discussionmentioning

confidence: 96%

“…HR1 could mediate fusion like SNARE proteins do, that is, by assembling like a zipper (which would be a homotypic complex in the case of HR1) across the membranes destined to fuse, forcing their close apposition and lipid mixing [3][4][5][6][7][8]. Alternatively, HR1 could mediate fusion by perturbing the lipid bilayer structure, as recently shown for a C-terminal amphipathic fragment of the ER membrane fusion protein Atlastin [56,57]. Such perturbation could occur when HR1 interacts with the membrane in which it is anchored and/or when HR1 interacts with the opposing membrane.…”

Section: Discussionmentioning

confidence: 99%

The heptad repeat domain 1 of Mitofusin has membrane destabilization function in mitochondrial fusion

et al. 2018

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Mitochondria are double-membrane-bound organelles that constantly change shape through membrane fusion and fission. Outer mitochondrial membrane fusion is controlled by Mitofusin, whose molecular architecture consists of an N-terminal GTPase domain, a first heptad repeat domain (HR1), two transmembrane domains, and a second heptad repeat domain (HR2). The mode of action of Mitofusin and the specific roles played by each of these functional domains in mitochondrial fusion are not fully understood. Here, using a combination of and fusion assays, we show that HR1 induces membrane fusion and possesses a conserved amphipathic helix that folds upon interaction with the lipid bilayer surface. Our results strongly suggest that HR1 facilitates membrane fusion by destabilizing the lipid bilayer structure, notably in membrane regions presenting lipid packing defects. This mechanism for fusion is thus distinct from that described for the heptad repeat domains of SNARE and viral proteins, which assemble as membrane-bridging complexes, triggering close membrane apposition and fusion, and is more closely related to that of the C-terminal amphipathic tail of the Atlastin protein.

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The Atlastin C-terminal Tail Is an Amphipathic Helix That Perturbs the Bilayer Structure during Endoplasmic Reticulum Homotypic Fusion

Cited by 47 publications

References 33 publications

The atlastin membrane anchor forms an intramembrane hairpin that does not span the phospholipid bilayer

The atlastin membrane anchor forms an intramembrane hairpin that does not span the phospholipid bilayer

Invited review: Mechanisms of GTP hydrolysis and conformational transitions in the dynamin superfamily

The heptad repeat domain 1 of Mitofusin has membrane destabilization function in mitochondrial fusion

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