?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F8694%2F&rft.title=Electron+Spin+Resonance+Analysis+of+Cu(II)+Coordination+in+Alzheimer's+Disease-Related+Peptides&rft.creator=Shin%2C+Byong-kyu&rft.description=We+exploit+electron+spin+resonance+(ESR)+to+understand+the+Cu(II)+coordination+of+Alzheimer's+disease-related+peptides.+It+has+been+observed+that+at+a+low+level+of+Cu(II)%2C+the+amyloid-%CE%B2+(A%CE%B2)+peptide+forms+fibrillar+aggregates%2C+whereas+amorphous+aggregates+are+dominant+at+a+high+level+of+Cu(II).+Three+histidine+residues%2C+His6%2C+His13%2C+and+His14%2C+are+believed+to+be+important+to+the+interaction+between+A%C3%A2+and+the+metal+ion.+The+role+of+each+histidine+residue+in+binding+to+Cu(II)+has+been+controversial+mainly+due+to+the+difficulty+in+elucidating+the+coordination+environment+of+Cu(II)+at+physiological+pH.+Using+pulsed+ESR%2C+we+precisely+examine+the+multiple+histidine+coordination+in+the+Cu(II)-A%CE%B2+complex.+For+the+first+time%2C+we+provide+direct+evidence+that+all+the+three+histidine+residues+coordinate+to+Cu(II)+at+physiological+pH.+Also%2C+the+relative+contribution+of+the+imidazole+ring+of+each+histidine+residue+to+the+Cu(II)+coordination+is+quantified.+To+establish+the+relative+contribution%2C+we+have+developed+a+method+that+examines+the+effects+of+multiple+histidine+coordination+on+electron+spin-echo+modulation.+The+ESR+results+reveal+that+His13+and+His14+simultaneously+coordinate+to+Cu(II)+in+a+significant+fraction+of+the+Cu(II)-A%CE%B2+complex+at+physiological+pH.+A+broad+interpretation+of+this+result+leads+to+the+hypothesis+that+the+simultaneous+Cu(II)-coordination+by+the+two+adjacent+residues+retards+the+formation+of+the+%CE%B2-sheet+structure+and+enables+a+substantial+amount+of+amorphous+aggregates+to+form.Next%2C+we+propose+potential+Cu(II)-binding+motifs+in+tau+protein+based+on+the+ESR+spectra+of+some+tau+fragments.+In+tau+protein%2C+there+are+four+pseudorepeats%2C+each+of+which+has+a+highly+conserved+18-amino-acid+segment.+The+ESR+results+show+that+the+18-amino-acid+sequence+in+each+pseudorepeat+has+a+good+binding+affinity+for+Cu(II).+In+particular%2C+pulsed+ESR+spectra+reveal+that+a+histidine+residue+and+a+backbone+amide+group+are+involved+in+the+Cu(II)+coordination+and+the+presence+of+the+intact+N-terminus+is+essential+for+the+stability+of+the+complex.+Also%2C+given+that+the+reported+dissociation+constants+of+some+Cu(II)-peptide+complexes+vary+by+several+orders+of+magnitude%2C+we+have+developed+a+simple+method+to+precisely+compare+the+dissociation+constants+at+physiological+pH.&rft.date=2011-09-30&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F8694%2F1%2FByong-kyuShinRevised080511.pdf&rft.identifier=++Shin%2C+Byong-kyu++(2011)+Electron+Spin+Resonance+Analysis+of+Cu(II)+Coordination+in+Alzheimer's+Disease-Related+Peptides.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++