Disulfide bond as a structural determinant of prion protein membrane insertion.
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.
Shin
Jae Yoon
JY
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Korea.
Shin
Jae Il
JI
Kim
Jun Seob
JS
Yang
Yoo Soo
YS
Shin
Yeon-Kyun
YK
Kim
Kyeong Kyu
KK
Lee
Sangho
S
Kweon
Dae-Hyuk
DH
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
D004220:Disulfides; D050505:Mutant Proteins; D011328:Prions