Nutrient deprivation alters the rate of COPII subunit recruitment at ER subdomains to tune secretory protein transport

Kasberg, William; Luong, Peter; Swift, Kevin A.; Audhya, Anjon

doi:10.1038/s41467-023-44002-7

Cited by 4 publications

References 82 publications

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Delineating the shape of COat Protein complex-II coated membrane bud

Paul,

Audhya,

Cui

2024

PNAS Nexus

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Curvature-generating proteins that direct membrane trafficking assemble on the surface of lipid bilayers to bud transport intermediates, which move protein and lipid cargoes from one cellular compartment to another. However, it remains unclear what controls the overall shape of the membrane bud once curvature induction has begun. In vitro experiments showed that excessive concentrations of the COPII protein Sar1 promoted the formation of membrane tubules from synthetic vesicles, while COPII-coated transport intermediates in cells are generally more spherical or lobed in shape. To understand the origin of these morphological differences, we employ atomistic, coarse-grained (CG), and continuum mesoscopic simulations of membranes in the presence of multiple curvature-generating proteins. We first characterize the membrane bending ability of amphipathic peptides derived from the amino terminus of Sar1, as a function of inter-peptide angle and concentration using an atomistic bicelle simulation protocol. Then, we employ CG simulations to reveal that Sec23 and Sec24 control the relative spacing between Sar1 protomers and form the inner-coat unit through an attachment with Sar1. Finally, using Dynamical Triangulated Surface (DTS) simulations based on the Helfrich Hamiltonian, we demonstrate that the uniform distribution of spacer molecules among curvature-generating proteins is crucial to the spherical budding of the membrane. Overall, our analyses suggest a new role for Sec23, Sec24 and cargo proteins in COPII mediated membrane budding process in which they act as spacers to preserve a dispersed arrangement of Sar1 protomers and help determine the overall shape of the membrane bud.

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Delineating the shape of COat Protein complex-II coated membrane bud

Paul,

Audhya,

Cui

2024

PNAS Nexus

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Delineating the shape of COPII coated membrane bud

Paul,

Audhya,

Cui

2024

Preprint

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Curvature-generating proteins that direct membrane trafficking assemble on the surface of lipid bilayers to bud transport intermediates, which move protein and lipid cargoes from one cellular compartment to another. Our recent study on the COPII protein Sar1 showed that the inserted volume of the protein into the membrane determines the degree of membrane bending. However, it is unclear what controls the overall shape of the membrane bud once curvature induction has begun. In vitro experiments showed that excessive concentrations of Sar1 promoted the formation of membrane tubules from synthetic vesicles, while COPII-coated transport intermediates in cells are generally more spherical or lobed in shape. To understand the origin of these morphological dissimilarities, we employ atomistic, coarse-grained (CG), and continuum mesoscopic simulations of membranes in the presence of multiple curvature-generating proteins. We first demonstrate the membrane bending ability of amphipathic peptides derived from the amino terminus of Sar1, as a function of inter-peptide angle and concentration using an atomistic bicelle simulation protocol. Then, we employ CG (MARTINI) simulations to reveal that Sec23 and Sec24 control the relative spacing between Sar1 protomers and form the inner-coat unit through an attachment with Sar1. Finally, using Dynamical Triangulated Surface (DTS) simulations based on the Helfrich Hamiltonian we demonstrate that the uniform distribution of spacer molecules among curvature-generating proteins is crucial to the spherical budding of the membrane. Overall, we show that Sec23 and Sec24 act as a spacer to preserve a dispersed arrangement of Sar1 protomers and to help determine the overall shape of the membrane bud.

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Multiple roles for TFG ring complexes in neuronal cargo trafficking

Zhang,

Lettman,

Schuh

et al. 2024

Preprint

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Pathological variants in Trk-fused gene (TFG) have been implicated in a variety of neurodegenerative conditions. In particular, mutations within its amino-terminal PB1 domain have been suggested to cause hereditary spastic paraplegia (HSP), resulting in progressive lower limb spasticity and weakness. The structural basis for this effect is unknown. Here, we combine X-ray crystallography and cryo-electron microscopy to determine a structural model of TFG, demonstrating the mechanism by which it forms octameric ring complexes. A network of electrostatic and hydrophobic interactions defines the interface between protomers. Moreover, we show that mutations identified previously in HSP patients disrupt this interface, destabilizing octamers, which ultimately leads to axonopathy. Surprisingly, the impacts of these variants are not equivalent in vivo, highlighting the existence of multiple, distinct mechanisms by which TFG mutations contribute to neurodegenerative disease.

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Nutrient deprivation alters the rate of COPII subunit recruitment at ER subdomains to tune secretory protein transport

Cited by 4 publications

References 82 publications

Delineating the shape of COat Protein complex-II coated membrane bud

Delineating the shape of COat Protein complex-II coated membrane bud

Delineating the shape of COPII coated membrane bud

Multiple roles for TFG ring complexes in neuronal cargo trafficking

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