Amyloid, The Amyloid B -Peptide and Alzheimer’s Disease: Structural Considerations - Molecules: Nucleation, Aggregation and Crystallization - page 290

Structure of A β in Fibrils

sheet con-
formation in the fibrils. Since amyloid is non-crystalline, it has not been
possible to obtain a detailed structure by X-ray crystallography. By using
cryo-EM in combination with advanced image processing, it was possi-
ble to visualize individual peptide strands in the fibril. In line with X-ray
diffraction data, the strands were aligned perpendicular to the fibril axis
with a repeat distance of 4.8 Å. In order to obtain more detailed infor-
mation, solid state NMR (SS-NMR) has been used in the last decade. By
SS-NMR analysis of fibrils formed from A

X-ray diffraction shows that the peptide is present in a cross- β

10-35 labeled with 13 C at
Gln15, Lys16, Leu17 or Val18, it was possible to obtain a high resolution
model of the central core of A

β

-sheet
structure with the amino acids aligned in register, i.e. Gln15 interacts
with Gln15 in adjacent strands (Benzinger et al ., 1998). These findings
were confirmed and extended by labeling A

β . This region showed a parallel β

10-35 at several different
positions, showing that the whole peptide was in a parallel

β

β -sheet con-

formation (Benzinger et al ., 2000). Also A β 1-40 as well as A β 1-42 fib-

rils were shown to have an in-register parallel -sheet conformation, but

in these cases the N-terminus was unstructured (Antzutkin et al ., 2000,
2002). The latter study suggested that the peptide had two parallel

β

-
sheet regions, 10-22 and 30-42 connected by a loop, which were folded
over each other. Such folding results in a protofilament with one polar
and one hydrophobic side. One strong driving force for peptide folding
and aggregation is to exclude hydrophobic surfaces from water, and it is
likely that the hydrophobic side of two such filaments would interact and
form a fibril. A similar but more refined model of A

β

1-40 fibrils was
suggested based on isotope dilution, restraints from SS-NMR measure-
ments in combination with molecular dynamics and energy minimization
calculations (Petkova et al ., 2002). Using hydrogen-exchange (see
below) and SS-NMR, data from previous SS-NMR studies and pairwise
substitutions of interacting residues, a detailed 3D structure of A

β

β 42 fib-

rils was presented (Lührs et al ., 2005) (Fig. 3).