title: Disulfide bond as a structural determinant of prion protein membrane insertion.
abstract: Conversion of the normal soluble form of prion protein, PrP (PrP(C)), to proteinase K-resistant form (PrP(Sc)) is a common molecular etiology of prion diseases. Proteinase K-resistance is attributed to a drastic conformational change from alpha-helix to beta-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 transmembrane 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 binding 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.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Jae Yoon
authors.initials: JY
authors.lastname: Shin
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Shin
authors.forename: Jun Seob
authors.initials: JS
authors.lastname: Kim
authors.forename: Yoo Soo
authors.initials: YS
authors.lastname: Yang
authors.forename: Yeon-Kyun
authors.initials: YK
authors.lastname: Shin
authors.forename: Kyeong Kyu
authors.initials: KK
authors.lastname: Kim
authors.forename: Sangho
authors.initials: S
authors.lastname: Lee
authors.forename: Dae-Hyuk
authors.initials: DH
authors.lastname: Kweon
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D004220:Disulfides / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D008647:Mesocricetus; D008954:Models, Biological; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary
chemical_list: D004220:Disulfides; D050505:Mutant Proteins; D011328:Prions