WORKLIST ENTRIES (1): BETAAMYLOID View alignment Beta-amyloid peptide (beta-APP) signature Type of fingerprint: COMPOUND with 3 elements Links: PRINTS; PR00203 AMYLOIDA4 INTERPRO; IPR001255 PDB; 1AAP 3Dinfo SCOP; 1AAP CATH; 1AAP Creation date 15-SEP-1993; UPDATE 06-JUN-1999 1. HARDY, J. Framing beta-amyloid. NAT.GENET. 1(4) 233-234 (1992). 2. ARISPE, N., ROJAS, E. AND POLLARD, H.B. Alzheimer's 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.BIOCHEM. 211 249-257 (1993). Beta-amyloid protein (beta-APP) is a 40-residue peptide implicated in the pathogenesis of Alzheimer's 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 . 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 . 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 . 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 FINGERPRINT INDEX 3| 10 10 10 2| 0 0 0 --+---------------- | 1 2 3 True positives.. A4_HUMAN Q60496 A4_SAISC P97487 A4_RAT A4_MOUSE O57394 Q91963 O73683 O93279 PROTEIN TITLES A4_HUMAN ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN PRECURSOR (PROTEASE N Q60496 ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN - CAVIA PORCELLUS (GU A4_SAISC ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN PRECURSOR [CONTAINS: P97487 HIPPOCAMPAL AMYLOID PROTEIN - MUS MUSCULUS (MOUSE). A4_RAT ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN HOMOLOG PRECURSOR (AM A4_MOUSE ALZHEIMER'S DISEASE AMYLOID A4 PROTEIN HOMOLOG PRECURSOR (AM O57394 EL AMYLOID PRECURSOR PROTEIN 699 - NARKE JAPONICA (ELECTRIC Q91963 APP747 - XENOPUS LAEVIS (AFRICAN CLAWED FROG). O73683 AMYLOID PRECURSOR PROTEIN - TETRAODON FLUVIATILIS (PUFFER FI O93279 BETA-AMYLOID PRECURSOR PROTEIN - FUGU RUBRIPES (JAPANESE PUF
SCAN HISTORY OWL21_1 2 50 NSINGLE OWL26_0 1 50 NSINGLE SPTR37_9f 2 11 NSINGLE INITIAL MOTIF SETS BETAAMYLOID1 Length of motif = 14 Motif number = 1 Beta amyloid peptide motif I - 1 PCODE ST INT FRHDSGYEVHHQKL A4_HUMAN 674 674 FGHDSGFEVRHQKL A4_MOUSE 674 674 FGHDSGFEVRHQKL A4_RAT 674 674 BETAAMYLOID2 Length of motif = 13 Motif number = 2 Beta amyloid peptide motif II - 1 PCODE ST INT VFFAEDVGSNKGA A4_HUMAN 688 0 VFFAEDVGSNKGA A4_MOUSE 688 0 VFFAEDVGSNKGA A4_RAT 688 0 BETAAMYLOID3 Length of motif = 13 Motif number = 3 Beta amyloid peptide motif III - 1 PCODE ST INT AIIGLMVGGVVIA A4_HUMAN 700 -1 AIIGLMVGGVVIA A4_MOUSE 700 -1 AIIGLMVGGVVIA A4_RAT 700 -1 FINAL MOTIF SETS BETAAMYLOID1 Length of motif = 14 Motif number = 1 Beta amyloid peptide motif I - 2 PCODE ST INT FRHDSGYEVHHQKL A4_HUMAN 675 675 FRHDSGYEVHHQKL Q60496 600 600 FRHDSGYEVHHQKL A4_SAISC 656 656 FGHDSGFEVRHQKL A4_MOUSE 675 675 FGHDSGFEVRHQKL A4_RAT 675 675 FGHDSGFEVRHQKL P97487 600 600 FQQDSGYEVHHQKL O57394 604 604 YRHDTAYEVHHQKL Q91963 652 652 DRQSTEYEVHHQKL O73683 685 685 KRQSAGYEVYHQKL O93279 642 642 BETAAMYLOID2 Length of motif = 13 Motif number = 2 Beta amyloid peptide motif II - 2 PCODE ST INT VFFAEDVGSNKGA A4_HUMAN 689 0 VFFAEDVGSNKGA Q60496 614 0 VFFAEDVGSNKGA A4_SAISC 670 0 VFFAEDVGSNKGA A4_MOUSE 689 0 VFFAEDVGSNKGA A4_RAT 689 0 VFFAEDVGSNKGA P97487 614 0 VFFPKDVGSNKGA O57394 618 0 VFFAEEVGSNKGA Q91963 666 0 VFFAEDVGSNKGA O73683 699 0 VFFADDVGSNKGA O93279 656 0 BETAAMYLOID3 Length of motif = 13 Motif number = 3 Beta amyloid peptide motif III - 2 PCODE ST INT AIIGLMVGGVVIA A4_HUMAN 701 -1 AIIGLMVGGVVIA Q60496 626 -1 AIIGLMVGGVVIA A4_SAISC 682 -1 AIIGLMVGGVVIA A4_MOUSE 701 -1 AIIGLMVGGVVIA A4_RAT 701 -1 AIIGLMVGGVVIA P97487 626 -1 AIIGLMVGGVVIA O57394 630 -1 AIIGLMVGGVVIA Q91963 678 -1 AIIGLMVGGVVIA O73683 711 -1 AIIGLMVGGVVIA O93279 668 -1
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