Mechanism of membrane-curvature generation by ER-tubule shaping proteins

Wang, Ning; Clark, Lindsay; Yuan, Gao; Kozlov, Michael M.; Shemesh, Tom; Rapoport, Tom A.

doi:10.1038/s41467-020-20625-y

Cited by 74 publications

(100 citation statements)

References 58 publications

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“…RHDs are also present in other proteins, such as reticulons and receptor expressionenhancing proteins, and in all cases they promote high membrane curvature, as observed in ER tubules or budding PPVs (Hu et al, 2008;Voeltz et al, 2006;Joshi et al, 2016;Wang et al, 2021). RHDs function as dimers, and different dimers induce distinct degrees of curvature, as shown recently for the RHDs of Yop1 and REEP5 (Wang et al, 2021). Pex30 RHD is necessary and sufficient to bind to Pex28/Pex32 and Pex29 (Figs.…”

Section: Discussionmentioning

confidence: 58%

“…Proteins of the Pex30 family associate with the ER membrane through an RHD formed by two pairs of closely spaced transmembrane segments (Joshi et al, 2016). RHDs are also present in other proteins, such as reticulons and receptor expressionenhancing proteins, and in all cases they promote high membrane curvature, as observed in ER tubules or budding PPVs (Hu et al, 2008;Voeltz et al, 2006;Joshi et al, 2016;Wang et al, 2021). RHDs function as dimers, and different dimers induce distinct degrees of curvature, as shown recently for the RHDs of Yop1 and REEP5 (Wang et al, 2021).…”

Section: Discussionmentioning

confidence: 66%

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Pex30-like proteins function as adaptors at distinct ER membrane contact sites

Ferreira

Carvalho

2021

Journal of Cell Biology

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Membrane lipids and proteins synthesized in the ER are used for de novo assembly of organelles, such as lipid droplets and peroxisomes. After assembly, the growth of these organelles is supported by ER-derived lipids transferred at membrane contact sites (MCSs). How ER sites for organelle biogenesis and lipid transfer are established and regulated is unclear. Here, we investigate how the ER membrane protein Pex30 and its family members Pex28, Pex29, Pex31, and Pex32 target and function at multiple MCSs. We show that different Pex30 complexes function at distinct ER domains and MCSs. Pex30 targets ER–peroxisome MCSs when bound to Pex28 and Pex32, organizes the nuclear–vacuolar junction when bound to Pex29, and promotes the biogenesis of lipid droplets independently of other family members. Importantly, the reticulon homology domain (RHD) mediates the assembly of the various Pex30 complexes. Given the role of RHD in membrane shaping, our findings offer a mechanistic link between MCS and regulation of membrane curvature.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 66%

Pex30-like proteins function as adaptors at distinct ER membrane contact sites

Ferreira

Carvalho

2021

Journal of Cell Biology

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“…These data indicate that Apq12 is at the heart of machinery that ensures NPC assembly, raising the important question about its molecular function. Because Apq12 does not have any sequence similarities to proteins with enzymatic activity, we have to assume that it functions either as a protein scaffold or impacts the shape of the NE as reported for reticulons that bend the ER by two cooperating pairs of trans-membrane domains with an adjacent AαH (Hu, Shibata et al, 2008, Wang, Clark et al, 2021. Following the rational that a combination of transmembrane domains and AαH could be the basis for the functional of Apq12, we analyzed Apq12 by the AmphipaSeeK program that predicated the presence of a short AαH connecting the two transmembrane domains.…”

Section: Discussionmentioning

confidence: 99%

“…1). However, the yeast reticulon Yop1 only deforms liposomes in the context of transmembrane domains and AαH (Wang et al, 2021). Thus, in future experiments it will be important to measure the membrane-deforming ability of the TM-AαH-TM core of Apq12.…”

Section: Discussionmentioning

confidence: 99%

A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis

Schiebel

Zhang

Khan

et al. 2021

Preprint

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The integral membrane protein Apq12 is an important nuclear envelope (NE)/ER modulator that cooperates with the nuclear pore complex (NPC) biogenesis factors Brl1 and Brr6. How Apq12 executes these functions is unknown. Here we identified a short amphipathic α-helix (AαH) in Apq12 that links the two transmembrane domains in the perinuclear space and has liposome-binding properties. Cells expressing an APQ12 (apq12-ah) version in which AαH is disrupted show NPC biogenesis and NE integrity defects, without impacting upon Apq12-ah topology or NE/ER localization. Overexpression of APQ12 but not apq12-ah triggers striking over-proliferation of the outer nuclear membrane (ONM)/ER and promotes accumulation of phosphatidic acid (PA) at the NE. Apq12 and Apq12-ah both associate with NPC biogenesis intermediates and removal of AαH increases both Brl1 levels and the interaction between Brl1 and Brr6. We conclude that the short amphipathic α-helix of Apq12 regulates the function of Brl1 and Brr6 and promotes PA accumulation at the NE during NPC biogenesis.

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“…topology, insert into the outer leaflet of the lipid bilayer as wedges 9,10,12,21 . The same curvature-promoting proteins also stabilize the high curvatures in the one-dimensional ER tubules 9,10 , which in mammalian cells are often taken as cylindrical tubules of ~50-100 nm diameter 2,7 .…”

mentioning

confidence: 99%

The endoplasmic reticulum adopts two distinct forms of tubules

Wang¹,

Zhao²,

Xiong³

et al. 2021

Preprint

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Being the largest and most expansive organelle in the cell, the endoplasmic reticulum (ER) carries diverse key functions from protein and lipid synthesis, protein folding and modification, transport, calcium storage, to organelle interactions1-6. The shaping mechanism of this complex, membrane-bounded organelle is thus of fundamental significance7-21. Using super-resolution microscopy, we uncover the coexistence of two distinct, well-defined forms of ER tubules in the mammalian cell. Whereas an ultrathin form, R1, is consistently covered by the membrane curvature-promoting protein Rtn4, in the second form, R2, Rtn4 curiously appears as two parallel lines at a conserved separation of ~105 nm over long ranges. The two tubule forms together account for ~90% of the total tubule lengths, with either one being dominant in different cell types. The R1-R2 dichotomy and the final tubule geometry are both co-regulated by Rtn4 and the ER sheet-maintaining protein Climp63, which respectively define the edge curvature and lumen height of the R2 tubules to generate a ribbon-like structure of well-defined width. The R1 and R2 tubules undergo active remodeling in the cell as they differently accommodate proteins, with the former effectively excluding ER-luminal proteins and ER-membrane proteins with large intraluminal domains. We thus unveil a dynamic ER-tubule structural dichotomy with intriguing functional implications.

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Mechanism of membrane-curvature generation by ER-tubule shaping proteins

Cited by 74 publications

References 58 publications

Pex30-like proteins function as adaptors at distinct ER membrane contact sites

Pex30-like proteins function as adaptors at distinct ER membrane contact sites

A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis

The endoplasmic reticulum adopts two distinct forms of tubules

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