Tài liệu Báo cáo khoa học: The Alzheimer b-peptide shows temperature-dependent transitions between

The Alzheimer b-peptide shows temperature-dependent

transitions between left-handed 31-helix, b-strand and

random coil secondary structures

Jens Danielsson, Ju¨ri Jarvet, Peter Damberg and Astrid Gra¨ slund

Department of Biochemistry and Biophysics, Stockholm University, Sweden

The amyloid b-peptide (Ab) is the major component of

the amyloid plaques found in the extracellular com￾partment in the brains of patients suffering from

Alzheimer’s disease. The Ab-peptide is a 39–42-residue

peptide with the sequence: DAEFRHDSGYEVHHQ

KLVFFAEDVGSNKGAIIGLMVGGVVIA(1–42). It

is cleaved from the Alzheimer’s precursor protein by

the proteases b- and c-secretase [1,2]. The Ab(1–40)

peptide has a hydrophilic N-terminal region and a

more hydrophobic C-terminal region. The peptide con￾tains a central hydrophobic cluster, residues 17–21,

which is suggested to play an important role in peptide

aggregation [3]. There is experimental evidence that

soluble oligomeric aggregates have toxic effects on

neurons and synapses [1,4]. The aggregation involves a

conformational change of the peptide structure to

b-sheet. Solid state NMR spectroscopy has shown that

fibrils of Ab contain parallel b-sheet structure, whereas

shorter fragment fibrils consist of antiparallel b-sheet

structure [5,6]. In vitro, the Ab monomer is in a domi￾nating random coil secondary structure in solution at

room temperature and physiological pH [7–9].

Keywords

amyloid b-peptide; b-strand; left-handed

31-helix; random coil; transition enthalpy

Correspondence

A. Gra¨slund, Department of Biochemistry

and Biophysics, Stockholm University,

S-106 91 Stockholm, Sweden

E-mail: [email protected]

(Received 13 April 2005, revised 26 May

2005, accepted 9 June 2005)

doi:10.1111/j.1742-4658.2005.04812.x

The temperature-induced structural transitions of the full length Alzheimer

amyloid b-peptide [Ab(1–40) peptide] and fragments of it were studied

using CD and 1

H NMR spectroscopy. The full length peptide undergoes

an overall transition from a state with a prominent population of left￾handed 31 (polyproline II; PII)-helix at 0
C to a random coil state at

60
C, with an average DH of 6.8 ± 1.4 kJÆmol)1 per residue, obtained by

fitting a Zimm–Bragg model to the CD data. The transition is noncoopera￾tive for the shortest N-terminal fragment Ab(1–9) and weakly cooperative

for Ab(1–40) and the longer fragments. By analysing the temperature￾dependent 3

JHNHa couplings and hydrodynamic radii obtained by NMR

for Ab(1–9) and Ab(12–28), we found that the structure transition includes

more than two states. The N-terminal hydrophilic Ab(1–9) populates PII￾like conformations at 0
C, then when the temperature increases, confor￾mations with dihedral angles moving towards b-strand at 20
C, and

approaches random coil at 60
C. The residues in the central hydrophobic

(18–28) segment show varying behaviour, but there is a significant contri￾bution of b-strand-like conformations at all temperatures below 20
C. The

C-terminal (29–40) segment was not studied by NMR, but from CD differ￾ence spectra we concluded that it is mainly in a random coil conformation

at all studied temperatures. These results on structural preferences and

transitions of the segments in the monomeric form of Ab may be related

to the processes leading to the aggregation and formation of fibrils in the

Alzheimer plaques.

Abbreviations

Ab-peptide, amyloid b-peptide; PII, polyproline II.

3938 FEBS Journal 272 (2005) 3938–3949 ª 2005 FEBS