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

Betancourt-Solis, Miguel A.; Desai, Tanvi; McNew, James A.

doi:10.1074/jbc.ra118.003812

Cited by 26 publications

(36 citation statements)

References 64 publications

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“…Similar branching defects have also been reported in C. elegans neurons mutated in atln-1, the ATL1 ortholog (Liu et al, 2019). In addition to their GTPase catalytic domain, ATLs also possess intramembrane domains, similar to those found in RTNs and REEPs, that are not only essential for ATL membrane fusion activity, but also could explain why ATL1 drives the generation of membrane tubules from proteoliposomes in vitro (Betancourt-Solis et al, 2018).…”

Section: Axonal Er Organizationsupporting

confidence: 69%

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

2020

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The physical continuity of axons over long cellular distances poses challenges for their maintenance. One organelle that faces this challenge is endoplasmic reticulum (ER); unlike other intracellular organelles, this forms a physically continuous network throughout the cell, with a single membrane and a single lumen. In axons, ER is mainly smooth, forming a tubular network with occasional sheets or cisternae and low amounts of rough ER. It has many potential roles: lipid biosynthesis, glucose homeostasis, a Ca 2+ store, protein export, and contacting and regulating other organelles. This tubular network structure is determined by ER-shaping proteins, mutations in some of which are causative for neurodegenerative disorders such as hereditary spastic paraplegia (HSP). While axonal ER shares many features with the tubular ER network in other contexts, these features must be adapted to the long and narrow dimensions of axons. ER appears to be physically continuous throughout axons, over distances that are enormous on a subcellular scale. It is therefore a potential channel for long-distance or regional communication within neurons, independent of action potentials or physical transport of cargos, but involving its physiological roles such as Ca 2+ or organelle homeostasis. Despite its apparent stability, axonal ER is highly dynamic, showing features like anterograde and retrograde transport, potentially reflecting continuous fusion and breakage of the network. Here we discuss the transport processes that must contribute to this dynamic behavior of ER. We also discuss the model that these processes underpin a homeostatic process that ensures both enough ER to maintain continuity of the network and repair breaks in it, but not too much ER that might disrupt local cellular physiology. Finally, we discuss how failure of ER organization in axons could lead to axon degenerative diseases, and how a requirement for ER continuity could make distal axons most susceptible to degeneration in conditions that disrupt ER continuity.

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Section: Axonal Er Organizationsupporting

confidence: 69%

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

2020

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“…In fact, the TM segments cannot be replaced by those from other proteins, and point mutations in these regions can reduce the efficiency of fusion (Liu et al, 2012). Recent experiments suggest that the TMs form two intramembrane hairpin loops, rather than two segments that completely span the membrane (Betancourt-Solis et al, 2018), which may explain their unique role in fusion. Taken together, it appears that a successful fusion event requires the cooperation of multiple trans-dimerization events: as one dimer reaches the transition state, other dimers forming nearby help to maintain the tethered state and add to the pulling force exerted on the opposing membranes.…”

Section: Membrane Fusion In Systems Reconstituted With Atl or Sey1mentioning

confidence: 99%

“…1B). Until recently, the membrane-bound region was thought to comprise two closely spaced TM segments, but it may actually consist of two intramembrane hairpin loops (Betancourt-Solis et al, 2018), similar to those in the Rtns and REEPs. Crystal structures and biochemical experiments have led to a model in which ATL molecules localized to different membranes dimerize through their GTPase domains, and undergo a conformational change during the GTPase cycle, thereby pulling the two membranes together and fusing them (for a review, see Hu and Rapoport, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Reconstituting the reticular ER network – mechanistic implications and open questions

Wang

Rapoport

2019

Journal of Cell Science

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The endoplasmic reticulum (ER) is a major membrane-bound organelle in all eukaryotic cells. This organelle comprises morphologically distinct domains, including the nuclear envelope and peripheral sheets and tubules. The tubules are connected by three-way junctions into a network. Several membrane proteins have been implicated in network formation; curvature-stabilizing proteins generate the tubules themselves, and membrane-anchored GTPases fuse tubules into a network. Recent experiments have shown that a tubular network can be formed with reconstituted proteoliposomes containing the yeast membrane-fusing GTPase Sey1 and a curvature-stabilizing protein of either the reticulon or REEP protein families. The network forms in the presence of GTP and is rapidly disassembled when GTP hydrolysis of Sey1 is inhibited, indicating that continuous membrane fusion is required for its maintenance. Atlastin, the ortholog of Sey1 in metazoans, forms a network on its own, serving both as a fusion and curvature-stabilizing protein. These results show that the reticular ER can be generated by a surprisingly small set of proteins, and represents an energydependent steady state between formation and disassembly. Models for the molecular mechanism by which curvature-stabilizing proteins cooperate with fusion GTPases to form a reticular network have been proposed, but many aspects remain speculative, including the function of additional proteins, such as the lunapark protein, and the mechanism by which the ER interacts with the cytoskeleton. How the nuclear envelope and peripheral ER sheets are formed remain major unresolved questions in the field. Here, we review reconstitution experiments with purified curvature-stabilizing proteins and fusion GTPases, discuss mechanistic implications and point out open questions.

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“…The TMSs are absent in solved Mfn crystal structures, therefore their role during mitochondrial fusion remains speculative. In contrast, the TMSs of ATL were claimed to be critical for ER membrane fusion and shown to be organised as an intra-membrane hairpin rather than a bilayer-spanning [ 20 ]. Thus, for Mfn, the presence of one or two TMSs might be crucial to understand the correct protein topology and the molecular movement upon GTP hydrolysis.…”

Section: Introductionmentioning

confidence: 99%

The GDP-Bound State of Mitochondrial Mfn1 Induces Membrane Adhesion of Apposing Lipid Vesicles through a Cooperative Binding Mechanism

et al. 2020

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Mitochondria are double-membrane organelles that continuously undergo fission and fusion. Outer mitochondrial membrane fusion is mediated by the membrane proteins mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), carrying a GTP hydrolyzing domain (GTPase) and two coiled-coil repeats. The detailed mechanism on how the GTP hydrolysis allows Mfns to approach adjacent membranes into proximity and promote their fusion is currently under debate. Using model membranes built up as giant unilamellar vesicles (GUVs), we show here that Mfn1 promotes membrane adhesion of apposing lipid vesicles. The adhesion forces were sustained by the GDP-bound state of Mfn1 after GTP hydrolysis. In contrast, the incubation with the GDP:AlF 4 − , which mimics the GTP transition state, did not induce membrane adhesion. Due to the flexible nature of lipid membranes, the adhesion strength depended on the surface concentration of Mfn1 through a cooperative binding mechanism. We discuss a possible scenario for the outer mitochondrial membrane fusion based on the modulated action of Mfn1.

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

Cited by 26 publications

References 64 publications

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

Reconstituting the reticular ER network – mechanistic implications and open questions

The GDP-Bound State of Mitochondrial Mfn1 Induces Membrane Adhesion of Apposing Lipid Vesicles through a Cooperative Binding Mechanism

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