Dataset Information

Cytoskeleton-dependent clustering of membrane-bound prion protein on the cell surface.

ABSTRACT: Prion diseases are a group of neurodegenerative disorders that infect animals and humans with proteinaceous particles called prions. Prions consist of scrapie prion protein (PrP^Sc), a misfolded version of the cellular prion protein (PrP^C). During disease progression, PrP^Sc replicates by interacting with PrP^C and inducing its conversion to PrP^Sc. Attachment of PrP^C to cellular membranes via a glycosylphosphatidylinositol (GPI) anchor is critical for the conversion of PrP^C into PrP^Sc. However, the mechanisms governing PrP^C conversion and replication on the membrane remain largely unclear. Here, a site-selectively modified PrP variant equipped with a fluorescent GPI anchor mimic (PrP-GPI) was employed to directly observe PrP at the cellular membrane in neuronal SH-SY5Y cells. PrP-GPI exhibits a cholesterol-dependent membrane accumulation and a cytoskeleton-dependent mobility. More specifically, inhibition of actin polymerization reduced the diffusion of PrP-GPI indicating protein clustering, which resembles the initial step of PrP aggregation and conversion into its pathogenic isoform. An intact actin cytoskeleton might therefore prevent conversion of PrP^C into PrP^Sc and offer new therapeutic angles.

SUBMITTER: Hackl S

PROVIDER: S-EPMC7988330 | biostudies-literature | 2021 Jan-Jun

REPOSITORIES: biostudies-literature

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Cytoskeleton-dependent clustering of membrane-bound prion protein on the cell surface.

Hackl Stefanie S Ng Xue Wen XW Lu Danqin D Wohland Thorsten T Becker Christian F W CFW

The Journal of biological chemistry 20210101

Prion diseases are a group of neurodegenerative disorders that infect animals and humans with proteinaceous particles called prions. Prions consist of scrapie prion protein (PrPSc), a misfolded version of the cellular prion protein (PrPC). During disease progression, PrPSc replicates by interacting with PrPC and inducing its conversion to PrPSc. Attachment of PrPC to cellular membranes via a glycosylphosphatidylinositol (GPI) anch ...[more]

PMID: 33539927

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Project description:Fission yeast serves as a model for how cellular polarization machinery consisting of signaling molecules and the actin and microtubule cytoskeleton regulates cell shape. In this work, we develop mathematical models to investigate how these cells maintain a tubular shape of approximately constant diameter. Many studies identify active Cdc42, found in a cap at the inner membrane of growing cell tips, as an important regulator of local cell wall remodeling, likely through control of exocyst tethering and the targeting of other polarity-enhancing structures. First, we show that a computational model with Cdc42-dependent local cell wall remodeling under turgor pressure predicts a relationship between spatial extent of growth signal and cell diameter that is in agreement with prior experiments. Second, we model the consequences of feedback between cell shape and distribution of Cdc42 growth signal at cell tips. We show that stability of cell diameter over successive cell divisions places restrictions on their mutual dependence. We argue that simple models where the spatial extent of the tip growth signal relies solely on geometrical alignment of confined microtubules might lead to unstable width regulation. Third, we study a computational model that combines a growth signal distributed over a characteristic length scale (as, for example, by a reaction-diffusion mechanism) with an axis-sensing microtubules system that places landmarks at positions where microtubule tips touch the cortex. A two-dimensional implementation of this model leads to stable cell diameter for a wide range of parameters. Changes to the parameters of this model reproduce straight, bent, and bulged cell shapes, and we discuss how this model is consistent with other observed cell shapes in mutants. Our work provides an initial quantitative framework for understanding the regulation of cell shape in fission yeast, and a scaffold for understanding this process on a more molecular level in the future.

Dataset Information

Cytoskeleton-dependent clustering of membrane-bound prion protein on the cell surface.

Publications

Cytoskeleton-dependent clustering of membrane-bound prion protein on the cell surface.

Similar Datasets

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