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Prion protein structural features indicate possible relations to signal peptidases


Glockshuber, Rudi; Hornemann, Simone; Billeter, Martin; Riek, Roland; Wider, Gerhard; Wüthrich, Kurt (1998). Prion protein structural features indicate possible relations to signal peptidases. FEBS letters, 426(3):291-296.

Abstract

Transmissible spongiform encephalopathies (TSEs) in mammalian species are believed to be caused by an oligomeric isoform, PrPSc, of the cellular prion protein, PrPC. One of the key questions in TSE research is how the observed accumulation of PrPSc, or possibly the concomitant depletion of PrPC can cause fatal brain damage. Elucidation of the so far unknown function of PrPC is therefore of crucial importance. PrPC is a membrane‐anchored cell surface protein that possesses a so far unique three‐dimensional structure. While the N‐terminal segment 23–120 of PrPC is flexibly disordered, its C‐terminal residues 121–231 form a globular domain with three α‐helices and a two‐stranded β‐sheet. Here we report the observation of structural similarities between the domain of PrP(121–231) and the soluble domains of membrane‐anchored signal peptidases. At the level of the primary structure we find 23% identity and 41% similarity between residues 121–217 of the C‐terminal domain of murine PrP and a catalytic domain of the rat signal peptidase. The invariant PrP residues Tyr‐128 and His‐177 align with the two presumed active‐site residues of signal peptidases and are in close spatial proximity in the three‐dimensional structure of PrP(121–231).

Abstract

Transmissible spongiform encephalopathies (TSEs) in mammalian species are believed to be caused by an oligomeric isoform, PrPSc, of the cellular prion protein, PrPC. One of the key questions in TSE research is how the observed accumulation of PrPSc, or possibly the concomitant depletion of PrPC can cause fatal brain damage. Elucidation of the so far unknown function of PrPC is therefore of crucial importance. PrPC is a membrane‐anchored cell surface protein that possesses a so far unique three‐dimensional structure. While the N‐terminal segment 23–120 of PrPC is flexibly disordered, its C‐terminal residues 121–231 form a globular domain with three α‐helices and a two‐stranded β‐sheet. Here we report the observation of structural similarities between the domain of PrP(121–231) and the soluble domains of membrane‐anchored signal peptidases. At the level of the primary structure we find 23% identity and 41% similarity between residues 121–217 of the C‐terminal domain of murine PrP and a catalytic domain of the rat signal peptidase. The invariant PrP residues Tyr‐128 and His‐177 align with the two presumed active‐site residues of signal peptidases and are in close spatial proximity in the three‐dimensional structure of PrP(121–231).

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Biophysics
Life Sciences > Structural Biology
Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Life Sciences > Genetics
Life Sciences > Cell Biology
Language:English
Date:24 April 1998
Deposited On:11 Nov 2020 10:45
Last Modified:12 Nov 2020 21:01
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0014-5793
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/s0014-5793(98)00372-x
PubMed ID:9600253

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