A Coincidence Detection Mechanism Controls PX-BAR Domain-Mediated Endocytic Membrane Remodeling via an Allosteric Structural Switch

Lo, Wen-Ting; Žagar, Andreja Vujičić; Gerth, Fabian; Lehmann, Martin; Puchkov, Dmytro; Krylova, Oxana; Freund, Christian; Scapozza, Léonardo; Vadas, Oscar; Haucke, Volker

doi:10.1016/j.devcel.2017.10.019

Cited by 34 publications

(26 citation statements)

References 31 publications

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“…Arrival of PI3KC2α follows that of clathrin with some delay to trigger the PI(3,4)P 2 -dependent recruitment of PX-BAR domain proteins SNX9 and SNX18. Lack of either PI3KC2α, or SNX9 or SNX18 stalls CME at the level of deeply invaginated CCPs that fail to form a narrow membrane neck, which provides a suitable substrate for endocytic vesicle scission by dynamin (Lo et al, 2017;Posor et al, 2013;Schoneberg et al, 2017). A similar CCP maturation phenotype is observed in cells depleted of the N-WASP-associated F-BAR domain protein FCHSD2, another effector of PI(3,4)P 2 (Almeida-Souza et al, 2018).…”

Section: Box 2 Lipid-mediated Regulation Of Cmementioning

confidence: 99%

Membrane remodeling in clathrin-mediated endocytosis

Haucke

Kozlov

2018

Journal of Cell Science

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109

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Clathrin-mediated endocytosis is an essential cellular mechanism by which all eukaryotic cells regulate their plasma membrane composition to control processes ranging from cell signaling to adhesion, migration and morphogenesis. The formation of endocytic vesicles and tubules involves extensive protein-mediated remodeling of the plasma membrane that is organized in space and time by protein-protein and protein-phospholipid interactions. Recent studies combining high-resolution imaging with genetic manipulations of the endocytic machinery and with theoretical approaches have led to novel multifaceted phenomenological data of the temporal and spatial organization of the endocytic reaction. This gave rise to various - often conflicting - models as to how endocytic proteins and their association with lipids regulate the endocytic protein choreography to reshape the plasma membrane. In this Review, we discuss these findings in light of the hypothesis that endocytic membrane remodeling may be determined by an interplay between protein-protein interactions, the ability of proteins to generate and sense membrane curvature, and the ability of lipids to stabilize and reinforce the generated membrane shape through adopting their lateral distribution to the local membrane curvature.

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Section: Box 2 Lipid-mediated Regulation Of Cmementioning

confidence: 99%

Membrane remodeling in clathrin-mediated endocytosis

Haucke

Kozlov

2018

Journal of Cell Science

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109

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“…Recent computational modeling and super-resolution imaging data show that local PI(3,4)P 2 synthesis by PI3KC2␣ at CCPs triggers the selective recruitment of the PX-BAR domain protein sorting nexin 9 (SNX9; and its close homolog SNX18) (18) to the invagination neck where its self-assembly regulates membrane constriction (19). Interestingly, the membrane-deforming activity of SNX9 is controlled by an allosteric structural switch involving coincident detection of the clathrin adaptor AP-2 and PI(3,4)P 2 at endocytic sites (20). This mechanism thus allows the spatiotemporal coupling of SNX9/18mediated membrane constriction to the progression of the endocytic pathway (21).…”

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confidence: 99%

Phosphoinositide conversion in endocytosis and the endolysosomal system

Wallroth

Haucke

2018

Journal of Biological Chemistry

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163

139

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Phosphoinositides (PIs) are phospholipids that perform crucial cell functions, ranging from cell migration and signaling to membrane trafficking, by serving as signposts of compartmental membrane identity. Although phosphatidylinositol 4,5-bisphosphate, 3-phosphate, and 3,5-bisphosphate are commonly considered as hallmarks of the plasma membrane, endosomes, and lysosomes, these compartments contain other functionally important PIs. Here, we review the roles of PIs in different compartments of the endolysosomal system in mammalian cells and discuss the mechanisms that spatiotemporally control PI conversion in endocytosis and endolysosomal membrane dynamics during endosome maturation and sorting. As defective PI conversion underlies human genetic diseases, including inherited myopathies, neurological disorders, and cancer, PI-converting enzymes represent potential targets for drug-based therapies.

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“…SNX9 has an N-terminus that consists of an SH3 domain followed by a low-complexity linker of 193 residues. The linker harbors a short acidic stretch that directly interacts with the SNX9 BAR dimer 11 , at a site that is equivalent to the region on the Mvp1 BAR domains that abut the bridge density, as assessed by hydrogen-deuterium exchange ( Supplementary Fig. 6e).…”

Section: Discussionmentioning

confidence: 99%

“…Autoinhibition in BAR domain-containing proteins has been reported 3 . For example, SNX9 is autoinhibited in solution and this has been shown to be due to the linker preceding the PX-BAR module 11 . Other examples include the PACSIN/syndapin F-BAR, the I-BAR IRSp53, and the Drosophila F-BAR protein Nervous Wreck [38][39][40] .…”

Section: Discussionmentioning

confidence: 99%

“…While some SNX-BAR proteins consist only of their PX-BAR modules, others, including those involved in retromer-mediated retrograde trafficking and autophagic processes 5,10 have, in addition, a low-complexity Nterminal region, the function of which is unclear. In the case of the endocytic SNX-BAR SNX9, this low-complexity region is involved in allosteric regulation of SNX9 membrane binding and remodeling activites 11 .…”

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confidence: 99%

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The cryo-EM structure of the SNX–BAR Mvp1 tetramer

et al. 2020

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Sorting nexins (SNX) are a family of PX domain-containing proteins with pivotal roles in trafficking and signaling. SNX-BARs, which also have a curvature-generating Bin/Amphiphysin/Rvs (BAR) domain, have membrane-remodeling functions, particularly at the endosome. The minimal PX-BAR module is a dimer mediated by BAR-BAR interactions. Many SNX-BAR proteins, however, additionally have low-complexity N-terminal regions of unknown function. Here, we present the cryo-EM structure of the full-length SNX-BAR Mvp1, which is an autoinhibited tetramer. The tetramer is a dimer of dimers, wherein the membrane-interacting BAR surfaces are sequestered and the PX lipid-binding sites are occluded. The N-terminal low-complexity region of Mvp1 is essential for tetramerization. Mvp1 lacking its N-terminus is dimeric and exhibits enhanced membrane association. Membrane binding and remodeling by Mvp1 therefore requires unmasking of the PX and BAR domain lipid-interacting surfaces. This work reveals a tetrameric configuration of a SNX-BAR protein that provides critical insight into SNX-BAR function and regulation.

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A Coincidence Detection Mechanism Controls PX-BAR Domain-Mediated Endocytic Membrane Remodeling via an Allosteric Structural Switch

Cited by 34 publications

References 31 publications

Membrane remodeling in clathrin-mediated endocytosis

Membrane remodeling in clathrin-mediated endocytosis

Phosphoinositide conversion in endocytosis and the endolysosomal system

The cryo-EM structure of the SNX–BAR Mvp1 tetramer

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