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Mol. Cells 2009; 27(6): 673-680

Published online June 30, 2009

https://doi.org/10.1007/s10059-009-0089-9

© The Korean Society for Molecular and Cellular Biology

Disulfide Bond as a Structural Determinant of Prion Protein Membrane Insertion

Jae Yoon Shin, Jae Il Shin, Jun Seob Kim, Yoo Soo Yang, Yeon-Kyun Shin, Kyeong Kyu Kim,
Sangho Lee, and Dae-Hyuk Kweon

Received: February 23, 2009; Revised: April 21, 2009; Accepted: April 22, 2009

Abstract

Conversion of the normal soluble form of prion protein, PrP (PrPC), to proteinase K-resistant form (PrPSc) is a common molecular etiology of prion diseases. Proteinase K-resistance is attributed to a drastic conformational change from ?-helix to ?-sheet and subsequent fibril formation. Compelling evidence suggests that membranes play a role in the conformational conversion of PrP. However, biophysical mechanisms underlying the conformational changes of PrP and membrane binding are still elusive. Recently, we demonstrated that the putative tran-smembrane domain (TMD; residues 111-135) of Syrian hamster PrP penetrates into the membrane upon the reduction of the conserved disulfide bond of PrP. To understand the mechanism underlying the membrane insertion of the TMD, here we explored changes in conformation and membrane bind-ing abilities of PrP using wild type and cysteine-free mutant. We show that the reduction of the disulfide bond of PrP removes motional restriction of the TMD, which might, in turn, expose the TMD into solvent. The released TMD then penetrates into the membrane. We suggest that the disulfide bond regulates the membrane binding mode of PrP by controlling the motional freedom of the TMD.

Keywords disulfide bond, membrane binding, prion protein, transmembrane domain

Article

Research Article

Mol. Cells 2009; 27(6): 673-680

Published online June 30, 2009 https://doi.org/10.1007/s10059-009-0089-9

Copyright © The Korean Society for Molecular and Cellular Biology.

Disulfide Bond as a Structural Determinant of Prion Protein Membrane Insertion

Jae Yoon Shin, Jae Il Shin, Jun Seob Kim, Yoo Soo Yang, Yeon-Kyun Shin, Kyeong Kyu Kim,
Sangho Lee, and Dae-Hyuk Kweon

Received: February 23, 2009; Revised: April 21, 2009; Accepted: April 22, 2009

Abstract

Conversion of the normal soluble form of prion protein, PrP (PrPC), to proteinase K-resistant form (PrPSc) is a common molecular etiology of prion diseases. Proteinase K-resistance is attributed to a drastic conformational change from ?-helix to ?-sheet and subsequent fibril formation. Compelling evidence suggests that membranes play a role in the conformational conversion of PrP. However, biophysical mechanisms underlying the conformational changes of PrP and membrane binding are still elusive. Recently, we demonstrated that the putative tran-smembrane domain (TMD; residues 111-135) of Syrian hamster PrP penetrates into the membrane upon the reduction of the conserved disulfide bond of PrP. To understand the mechanism underlying the membrane insertion of the TMD, here we explored changes in conformation and membrane bind-ing abilities of PrP using wild type and cysteine-free mutant. We show that the reduction of the disulfide bond of PrP removes motional restriction of the TMD, which might, in turn, expose the TMD into solvent. The released TMD then penetrates into the membrane. We suggest that the disulfide bond regulates the membrane binding mode of PrP by controlling the motional freedom of the TMD.

Keywords: disulfide bond, membrane binding, prion protein, transmembrane domain

Mol. Cells
Nov 30, 2022 Vol.45 No.11, pp. 763~867
COVER PICTURE
Naive (cyan) and axotomized (magenta) retinal ganglion cell axons in Xenopus tropicalis (Choi et al., pp. 846-854).

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