| Literature References | 1. HARDY, J.
Framing beta-amyloid.
NATURE GENET.(1) 233-234 (1992).
2. ARISPE, N., ROJAS, E. AND POLLARD, H.B.
Alzheimers disease amyloid beta-protein forms calcium channels in bilayer
membranes: blockade by tromethamine and aluminum.
PROC.NATL.ACAD.SCI.U.S.A. 90 567-571 (1993).
3. OTVOS, L., SZENDREI, G.I., LEE, V.M.-Y AND MANTSCH, H.H.
Human and rodent Alzheimer beta-amyloid peptides acquire distinct
conformations in membrane-mimicking solvents.
EUR.J.BIOCHEMISTRY 211 249-257 (1993).
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| Documentation | Beta-amyloid protein (beta-APP) is a 40-residue peptide implicated in the
pathogenesis of Alzheimers disease (AD) and aged Down's Syndrome (which is
promoted by the acquisition of an additional copy of chromosome 21) [1-3].
The peptide is a proteolytic product of the much larger amyloid precursor
protein (APP) encoded by a gene on chromosome 21. In AD, pathologically the
brain is characterised by extracellular amyloid plaques, intraneuronal
neurofibrillary tangles, and vascular and neuronal damage. The major
protein found within these deposits is a small, highly aggregating peptide
(beta-APP), which is thought to be derived from aberrant catabolism of its
precursor.
The exact function of APP is unknown, but it may mediate cell-cell inter-
actions. The protein comprises a large extracellular N-terminal domain, and
a short hydrophobic membrane-spanning domain, followed by a short
C-terminal region - beta-APP both precedes and forms part of the trans-
membrane region. Little is known about its structure, but studies on a
synthetic peptide have shown that it can express different proportions of
alpha-helix and beta-sheet, depending on physiologically relevant environ-
mental variables, such as ionic strength, pH and hydrophobicity [2]. The
extracellular 28-residue region of the peptide is organised in a cross beta-
structure, while the C-terminal portion is believed to span the membrane
via a hydrophobic alpha-helical domain. Assemblies of different numbers of
such synthetic peptides have been shown to form cation-selective ion
channels across planar lipid bilayers [2].
Brain deposits of beta-APP in amyloid fibrils are common in humans,
monkeys, dogs and bears, but similar accumulations are rare in rodent
brains. The primary sequence of the rodent peptide differs at only 3
positions compared with its human counterpart, and it is believed that
these subtle inter-species differences may account for the inability of
the rodent peptide to form amyloid fibrils in situ. Specifically, the
human peptide, but not the rodent homologue, is capable of forming a
beta-sheet structure at low peptide concentration. Thus, a specific
amino-acid sequence is a critical determinant of amyloidogenesis [3].
BETAAMYLOID is a 3-element fingerprint that provides a signature for the
beta-amyloid peptide. The fingerprint was derived from an initial alignment
of 3 sequences: the motifs completely span the 40-residue peptide, the
first two corresponding to the sheet-forming hydrophilic region, and the
third to the alpha-helical hydrophobic C-terminus. Two iterations on
OWL21.1 were required to reach convergence, at which point a true set
comprising 7 sequences was identified. A single partial match was also
found, A44017, a beta-APP fragment lacking the portion of sequence bearing
motif 1.
An update on SPTR37_9f identified a true set of 10 sequences.
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