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PR00204

Identifier
BETAAMYLOID  [View Relations]  [View Alignment]  
Accession
PR00204
No. of Motifs
3
Creation Date
15-SEP-1993  (UPDATE 06-JUN-1999)
Title
Beta-amyloid peptide (beta-APP) signature
Database References
PRINTS; PR00203 AMYLOIDA4
INTERPRO; IPR001255
PDB; 1AAP
SCOP; 1AAP
CATH; 1AAP
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).

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.
Summary Information
10 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3101010
2000
123
True Positives
A4_HUMAN      A4_MOUSE      A4_RAT        A4_SAISC      
O57394 O73683 O93279 P97487
Q60496 Q91963
Sequence Titles
A4_HUMAN    ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN PRECURSOR (PROTEASE NEXIN-II) (PN-II) (APPI) [CONTAINS: BETA-AMYLOID PROTEIN (BETA-APP)] - HOMO SAPIENS (HUMAN). 
A4_MOUSE ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN HOMOLOG PRECURSOR (AMYLOIDOGENIC GLYCOPROTEIN) (AG) - MUS MUSCULUS (MOUSE).
A4_RAT ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN HOMOLOG PRECURSOR (AMYLOIDOGENIC GLYCOPROTEIN) (AG) - RATTUS NORVEGICUS (RAT).
A4_SAISC ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN PRECURSOR [CONTAINS: BETA- AMYLOID PROTEIN (BETA-APP)] - SAIMIRI SCIUREUS (COMMON SQUIRREL MONKEY).
O57394 EL AMYLOID PRECURSOR PROTEIN 699 - NARKE JAPONICA (ELECTRIC RAY).
O73683 AMYLOID PRECURSOR PROTEIN - TETRAODON FLUVIATILIS (PUFFER FISH).
O93279 BETA-AMYLOID PRECURSOR PROTEIN - FUGU RUBRIPES (JAPANESE PUFFERFISH) (TAKIFUGU RUBRIPES).
P97487 HIPPOCAMPAL AMYLOID PROTEIN - MUS MUSCULUS (MOUSE).
Q60496 ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN - CAVIA PORCELLUS (GUINEA PIG).
Q91963 APP747 - XENOPUS LAEVIS (AFRICAN CLAWED FROG).
Scan History
OWL21_1    2  50   NSINGLE    
OWL26_0 1 50 NSINGLE
SPTR37_9f 2 11 NSINGLE
Initial Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
FRHDSGYEVHHQKL A4_HUMAN 674 674 -
FGHDSGFEVRHQKL A4_MOUSE 674 674 -
FGHDSGFEVRHQKL A4_RAT 674 674 -

Motif 2 width=13
Element Seqn Id St Int Rpt
VFFAEDVGSNKGA A4_HUMAN 688 0 -
VFFAEDVGSNKGA A4_MOUSE 688 0 -
VFFAEDVGSNKGA A4_RAT 688 0 -

Motif 3 width=13
Element Seqn Id St Int Rpt
AIIGLMVGGVVIA A4_HUMAN 700 -1 -
AIIGLMVGGVVIA A4_MOUSE 700 -1 -
AIIGLMVGGVVIA A4_RAT 700 -1 -
Final Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
FRHDSGYEVHHQKL A4_HUMAN 674 674 -
FRHDSGYEVHHQKL Q60496 600 600 -
FRHDSGYEVHHQKL A4_SAISC 656 656 -
FGHDSGFEVRHQKL A4_MOUSE 674 674 -
FGHDSGFEVRHQKL A4_RAT 674 674 -
FGHDSGFEVRHQKL P97487 600 600 -
FQQDSGYEVHHQKL O57394 604 604 -
YRHDTAYEVHHQKL Q91963 652 652 -
DRQSTEYEVHHQKL O73683 685 685 -
KRQSAGYEVYHQKL O93279 642 642 -

Motif 2 width=13
Element Seqn Id St Int Rpt
VFFAEDVGSNKGA A4_HUMAN 688 0 -
VFFAEDVGSNKGA Q60496 614 0 -
VFFAEDVGSNKGA A4_SAISC 670 0 -
VFFAEDVGSNKGA A4_MOUSE 688 0 -
VFFAEDVGSNKGA A4_RAT 688 0 -
VFFAEDVGSNKGA P97487 614 0 -
VFFPKDVGSNKGA O57394 618 0 -
VFFAEEVGSNKGA Q91963 666 0 -
VFFAEDVGSNKGA O73683 699 0 -
VFFADDVGSNKGA O93279 656 0 -

Motif 3 width=13
Element Seqn Id St Int Rpt
AIIGLMVGGVVIA A4_HUMAN 700 -1 -
AIIGLMVGGVVIA Q60496 626 -1 -
AIIGLMVGGVVIA A4_SAISC 682 -1 -
AIIGLMVGGVVIA A4_MOUSE 700 -1 -
AIIGLMVGGVVIA A4_RAT 700 -1 -
AIIGLMVGGVVIA P97487 626 -1 -
AIIGLMVGGVVIA O57394 630 -1 -
AIIGLMVGGVVIA Q91963 678 -1 -
AIIGLMVGGVVIA O73683 711 -1 -
AIIGLMVGGVVIA O93279 668 -1 -