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PR01816

Identifier
BACE1  [View Relations]  [View Alignment]  
Accession
PR01816
No. of Motifs
7
Creation Date
18-DEC-2002  (UPDATE 09-APR-2009)
Title
Beta-site APP cleaving enzyme 1 (BACE1) signature
Database References
PRINTS; PR00792 PEPSIN; PR01815 BACEFAMILY
PRODOM; PD336879; PD459648
MIM; 604252
Literature References
1. GLENNER, G. AND WONG, C.
Alzheimer's disease: initial report of the purification and characterization
of a novel cerebrovascular amyloid protein.
BIOCHEM.BIOPHYS.RES.COMMUN. 120 885-890 (1984).
 
2. KANG, J., LEMAIRE, H., UNTERBECK, A., SALBAUM, J., MASTERS, C., 
GRZESCHIK, K., MULTHAUP, G., BEYREUTHER, K. AND MULLER-HILL, B.
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-
surface receptor.
NATURE 325 733-736 (1987).
 
3. VASSAR, R., BENNETT, B., BABU-KAHN, S., KAHN, S., MENDIAZ, E., DENIS, P.,
TEPLOW, D., ROSS, S., AMARANTE, P., LOELOFF, R., LUO, Y., FISHER, S., 
FULLER, J., EDENSON, S., LILE, J., JAROSINSKI, M., BIERE, A., CURRAN, E., 
BURGESS, T., LOUIS, J., COLLINS, F., TREANOR, J., ROGERS, G. AND CITRON, M.
Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the 
transmembrane aspartic protease BACE.
SCIENCE 286 735-741 (1999).
 
4. HUSSAIN, I., POWELL, D., HOWLETT, D., TEW, D., MEEK, T., CHAPMAN, C., 
GLOGER, I., MURPHY, K., SOUTHAN C., RYAN, D., SMITH, T., SIMMONS, D.,
WALSH, F., DINGWALL, C. AND CHRISTIE, G.
Identification of a novel aspartic protease (Asp 2) as beta-secretase.
MOL.CELL.NEUROSCI. 14 419-427 (1999).
 
5. YAN, R., BIENKOWSKI, M., SHUCK, M., MIAO, H., TORY, M., PAULEY, A., 
BRASHIER, J., STRATMAN, N., MATHEWS, W., BUHL, A., CARTER, D., 
TOMASSELLI, A., PARODI, L., HEINRIKSON, R. AND GURNEY, M.
Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase 
activity.
NATURE 402 533-537 (1999).
 
6. CITRON, M.
Beta-secretase as a target for the treatment of Alzheimer's disease.
J.NEUROSCI.RES. 70 373-379 (2002).
 
7. LUO, Y., BOLON, B., KAHN, S., BENNETT, B., BABU-KHAN, S., DENIS, P., 
FAN, W., KHA, H., ZHANG, J., GONG, Y., MARTIN, L., LOUIS, J., YAN, Q.,
RICHARDS, W., CITRON, M. AND VASSAR, R.
Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal 
phenotype and abolished beta-amyloid generation.
NAT.NEUROSCI. 4 231-232 (2001).

Documentation
One of the major neuropathological hallmarks of Alzheimer's disease (AD)
is the progressive formation in the brain of insoluble amyloid plaques and 
vascular deposits consisting of beta-amyloid protein (beta-APP) [1].
Production of beta-APP requires proteolytic cleavage of the large type-1 
transmembrane (TM) protein amyloid precursor protein (APP) [2]. This process
is performed by a variety of enzymes known as secretases. To initiate 
beta-APP formation, beta-secretase cleaves APP to release a soluble 
N-terminal fragment (APPsBeta) and a C-terminal fragment that remains 
membrane bound. This fragment is subsequently cleaved by gamma-secretase 
to liberate beta-APP.
 
Several independent studies identified a novel TM aspartic protease as the
major beta-secretase [3,4,5]. This protein, termed beta-site APP cleaving
enzyme 1 (BACE1), shares 64% amino acid sequence similarity with a second
enzyme, termed BACE2. Together, BACE1 and BACE2 define a novel family of 
aspartyl proteases [6]. Both enzymes share significant sequence similarity
with other members of the pepsin family of aspartyl proteases and contain 
the two characteristic D(T/S)G(T/S) motifs that form the catalytic site.
However, by contrast with other aspartyl proteases, BACE1 and BACE2 are
type I TM proteins. Each protein comprises a large lumenal domain containing
the active centre, a single TM domain and a small cytoplasmic tail.
 
BACE1, also termed Asp2 and memapsin-2, has a broad tissue distribution, 
with brain expression levels moderately higher than those of peripheral 
tissues [3]. Mice deficient in BACE1 are healthy, fertile, and appear normal
in gross anatomy, tissue histology and clinical chemistry [7]. BACE1 -/- 
mice that are also hemizygous for an amyloid precursor protein transgene 
lack brain beta-amyloid and beta-secretase-cleaved APP C-terminal fragments
[7]. These findings substantiate the theory that BACE1 acts as the major 
beta-secretase in vivo, and suggest that therapeutic inhibition of BACE1 as
a potential treatment for Alzheimer's disease may be free of mechanism-
based toxicity.
 
BACE1 is a 7-element fingerprint that provides a signature for beta-site APP
cleaving enzyme 1 (BACE1). The fingerprint was derived from an initial
alignment of 10 sequences: the motifs were drawn from conserved regions 
spanning virtually the full alignment length, focusing on those sections
that characterise BACE1 but distinguish it from other BACE family members.
Two iterations on SPTR55_38f were required to reach convergence, at which
point a true set comprising 12 sequences was identified. Two partial matches
were also found, both of which are BACE family members that fail to make
significant matches with 3 or more motifs.
Summary Information
  12 codes involving  7 elements
0 codes involving 6 elements
0 codes involving 5 elements
1 codes involving 4 elements
0 codes involving 3 elements
1 codes involving 2 elements
Composite Feature Index
712121212121212
60000000
50000000
40001111
30000000
21100000
1234567
True Positives
A0M8W7_HUMAN  BACE1_BOVIN   BACE1_CAVPO   BACE_HUMAN    
BACE_MOUSE BACE_RAT Q0P4T5_XENTR Q6NZT7_DANRE
Q8BQY4_MOUSE Q8C4F4_MOUSE Q8C7R1_MOUSE Q8IYC8_HUMAN
True Positive Partials
Codes involving 4 elements
Q9CUU5_MOUSE
Codes involving 2 elements
Q76KP0_HUMAN
Sequence Titles
A0M8W7_HUMAN Beta-site APP-cleaving enzyme 1 (Beta-site APP-cleaving enzyme 1, isoform CRA_d) - Homo sapiens (Human). 
BACE1_BOVIN Beta-secretase 1 precursor (EC 3.4.23.46) (Beta-site APP cleaving enzyme 1) (Beta-site amyloid precursor protein cleaving enzyme 1) (Membrane-associated aspartic protease 2) (Memapsin-2) - Bos taurus (Bovine).
BACE1_CAVPO Beta-secretase 1 precursor (EC 3.4.23.46) (Beta-site APP cleaving enzyme 1) (Beta-site amyloid precursor protein cleaving enzyme 1) (Membrane-associated aspartic protease 2) (Memapsin-2) - Cavia porcellus (Guinea pig).
BACE_HUMAN Beta-secretase precursor (EC 3.4.23.-) (Beta-site APP cleaving enzyme) (Beta-site amyloid precursor protein cleaving enzyme) (Aspartyl protease 2) (Asp 2) (ASP2) (Membrane-associated aspartic protease 2) (Memapsin-2) - Homo sapiens (Human).
BACE_MOUSE Beta-secretase precursor (EC 3.4.23.-) (Beta-site APP cleaving enzyme) (Beta-site amyloid precursor protein cleaving enzyme) (Aspartyl protease 2) (Asp 2) (ASP2) (Membrane-associated aspartic protease 2) (Memapsin-2) - Mus musculus (Mouse).
BACE_RAT Beta-secretase precursor (EC 3.4.23.-) (Beta-site APP cleaving enzyme) (Beta-site amyloid precursor protein cleaving enzyme) (Aspartyl protease 2) (Asp 2) (ASP2) (Membrane-associated aspartic protease 2) (Memapsin-2) - Rattus norvegicus (Rat).
Q0P4T5_XENTR Beta-site APP-cleaving enzyme 1 - Xenopus tropicalis (Western clawed frog) (Silurana tropicalis).
Q6NZT7_DANRE Zgc:77409 - Danio rerio (Zebrafish) (Brachydanio rerio).
Q8BQY4_MOUSE Adult male corpora quadrigemina cDNA, RIKEN full-length enriched library, clone:B230346M13 product:beta-site APP cleaving enzyme, full insert sequence - Mus musculus (Mouse).
Q8C4F4_MOUSE 0 day neonate cerebellum cDNA, RIKEN full-length enriched library, clone:C230037E16 product:beta-site APP cleaving enzyme, full insert sequence - Mus musculus (Mouse).
Q8C7R1_MOUSE 12 days embryo spinal cord cDNA, RIKEN full-length enriched library, clone:C530008K17 product:beta-site APP cleaving enzyme, full insert sequence - Mus musculus (Mouse).
Q8IYC8_HUMAN Beta-site APP-cleaving enzyme 1 - Homo sapiens (Human).

Q9CUU5_MOUSE Adult male brain cDNA, RIKEN full-length enriched library, clone:3526402A15 product:beta-site APP cleaving enzyme, full insert sequence - Mus musculus (Mouse).

Q76KP0_HUMAN Beta-site APP cleaving enzyme isoform I-127 - Homo sapiens (Human).
Scan History
SPTR55_38f 2  100  NSINGLE    
Initial Motifs
Motif 1  width=16
Element Seqn Id St Int Rpt
SSNFAVGAAPHPFLHR BACE_MOUSE 96 96 -
SSNFAVGAAPHPFLHR Q8C7R1_MOUSE 96 96 -
SSNFAVGAAPHPFLHR Q8BQY4_MOUSE 96 96 -
SSNFAVGAAPHPFLHR BACE_RAT 96 96 -
SSNFAVGAAPHPFLHR BACE1_BOVIN 96 96 -
SSNFAVGAAPHPFLHR A0M8W7_HUMAN 96 96 -
SSNFAVGAAPHPFLHR BACE_HUMAN 96 96 -
SSNFAVGAAPHPFLHR Q8IYC8_HUMAN 96 96 -
SSNFAVGAAPHPFLKR Q0P4T5_XENTR 97 97 -
SSNFAVGAAAHPFLHR Q6NZT7_DANRE 101 101 -

Motif 2 width=11
Element Seqn Id St Int Rpt
RQLSSTYRDLR BACE_MOUSE 115 3 -
RQLSSTYRDLR Q8C7R1_MOUSE 115 3 -
RQLSSTYRDLR Q8BQY4_MOUSE 115 3 -
RQLSSTYRDLR BACE_RAT 115 3 -
RQLSSTYRDLR BACE1_BOVIN 115 3 -
RQLSSTYRDLR A0M8W7_HUMAN 115 3 -
RQLSSTYRDLR BACE_HUMAN 115 3 -
RQLFSTYRDLR Q8IYC8_HUMAN 115 3 -
RQHSRTYRDVR Q0P4T5_XENTR 116 3 -
RSLSSSYRDLG Q6NZT7_DANRE 120 3 -

Motif 3 width=21
Element Seqn Id St Int Rpt
SLQLCGAGFPLNQTEALASVG BACE_MOUSE 212 86 -
SLQLCGAGFPLNQTEALASVG Q8C7R1_MOUSE 212 86 -
SLQLCGAGFPLNQTEALASVG Q8BQY4_MOUSE 212 86 -
SLQLCGAGFPLNQTEALASVG BACE_RAT 212 86 -
SLQLCGAGFPLNQSEALASVG BACE1_BOVIN 212 86 -
SLQLCGAGFPLNQSEVLASVG A0M8W7_HUMAN 212 86 -
SLQLCGAGFPLNQSEVLASVG BACE_HUMAN 212 86 -
SLQLCGAGFPLNQSEVLASVG Q8IYC8_HUMAN 212 86 -
SLQLCGTGFHFNESDTSASVG Q0P4T5_XENTR 213 86 -
SLQLCGAGYNHNYSTGSSSTV Q6NZT7_DANRE 217 86 -

Motif 4 width=15
Element Seqn Id St Int Rpt
TILPQQYLRPVEDVA BACE_MOUSE 360 127 -
TILPQQYLRPVEDVA Q8C7R1_MOUSE 360 127 -
TILPQQYLRPVEDVA Q8BQY4_MOUSE 360 127 -
TILPQQYLRPVEDVA BACE_RAT 360 127 -
TILPQQYLRPVEDVA BACE1_BOVIN 360 127 -
TILPQQYLRPVEDVA A0M8W7_HUMAN 360 127 -
TILPQQYLRPVEDVA BACE_HUMAN 360 127 -
TILPQQYLRPVEDVA Q8IYC8_HUMAN 360 127 -
TILPQQYLRPVEDIA Q0P4T5_XENTR 361 127 -
SILPQQYLRPVEDVA Q6NZT7_DANRE 366 128 -

Motif 5 width=13
Element Seqn Id St Int Rpt
FAVSACHVHDEFR BACE_MOUSE 415 40 -
FAVSACHVHDEFR Q8C7R1_MOUSE 415 40 -
FAVSACHVHDEFR Q8BQY4_MOUSE 415 40 -
FAVSACHVHDEFR BACE_RAT 415 40 -
FAVSACHVHDEFR BACE1_BOVIN 415 40 -
FAVSACHVHDEFR A0M8W7_HUMAN 415 40 -
FAVSACHVHDEFR BACE_HUMAN 415 40 -
FAVSACHVHDEFR Q8IYC8_HUMAN 415 40 -
FAVSTCHVHDYFR Q0P4T5_XENTR 416 40 -
FAVSTCHVHDEFR Q6NZT7_DANRE 421 40 -

Motif 6 width=20
Element Seqn Id St Int Rpt
PFVTADMEDCGYNIPQTDES BACE_MOUSE 434 6 -
PFVTADMEDCGYNIPQTDES Q8C7R1_MOUSE 434 6 -
PFVTADMEDCGYNIPQTDES Q8BQY4_MOUSE 434 6 -
PFVTADMEDCGYNIPQTDES BACE_RAT 434 6 -
PFVTPDMEDCGYNIPQTDES BACE1_BOVIN 434 6 -
PFVTLDMEDCGYNIPQTDES A0M8W7_HUMAN 434 6 -
PFVTLDMEDCGYNIPQTDES BACE_HUMAN 434 6 -
PFVTLDMEDCGYNIPQTDES Q8IYC8_HUMAN 434 6 -
PFFASDLEDCGYNTPQLDES Q0P4T5_XENTR 435 6 -
PFHGLDLEDCGYNVPQTDES Q6NZT7_DANRE 440 6 -

Motif 7 width=21
Element Seqn Id St Int Rpt
LMTIAYVMAAICALFMLPLCL BACE_MOUSE 455 1 -
LMTIAYVMAAICALFMLPLCL Q8C7R1_MOUSE 455 1 -
LMTIAYVMAAICALFMLPLCL Q8BQY4_MOUSE 455 1 -
LMTIAYVMAAICALFMLPLCL BACE_RAT 455 1 -
LMTIAYVMAAICALFMLPLCL BACE1_BOVIN 455 1 -
LMTIAYVMAAICALFMLPLCL A0M8W7_HUMAN 455 1 -
LMTIAYVMAAICALFMLPLCL BACE_HUMAN 455 1 -
LMTIAYVMAAICALFMLPLCL Q8IYC8_HUMAN 455 1 -
LMTTAYVMAGVCALFMLPLCL Q0P4T5_XENTR 456 1 -
LMTIAYIMAGICALFMLPLCV Q6NZT7_DANRE 461 1 -
Final Motifs
Motif 1  width=16
Element Seqn Id St Int Rpt
SSNFAVGAAPHPFLHR BACE_MOUSE 96 96 -
SSNFAVGAAPHPFLHR Q8C7R1_MOUSE 96 96 -
SSNFAVGAAPHPFLHR Q8C4F4_MOUSE 96 96 -
SSNFAVGAAPHPFLHR Q8BQY4_MOUSE 96 96 -
SSNFAVGAAPHPFLHR BACE_RAT 96 96 -
SSNFAVGAAPHPFLHR BACE1_BOVIN 96 96 -
SSNFAVGAAPHPFLHR A0M8W7_HUMAN 96 96 -
SSNFAVGAAPHPFLHR BACE_HUMAN 96 96 -
SSNFAVGAAPHPFLHR Q8IYC8_HUMAN 96 96 -
SSNFAVGAAPHPFLHR BACE1_CAVPO 93 93 -
SSNFAVGAAPHPFLKR Q0P4T5_XENTR 97 97 -
SSNFAVGAAAHPFLHR Q6NZT7_DANRE 101 101 -

Motif 2 width=11
Element Seqn Id St Int Rpt
RQLSSTYRDLR BACE_MOUSE 115 3 -
RQLSSTYRDLR Q8C7R1_MOUSE 115 3 -
RQLSSTYRDLR Q8C4F4_MOUSE 115 3 -
RQLSSTYRDLR Q8BQY4_MOUSE 115 3 -
RQLSSTYRDLR BACE_RAT 115 3 -
RQLSSTYRDLR BACE1_BOVIN 115 3 -
RQLSSTYRDLR A0M8W7_HUMAN 115 3 -
RQLSSTYRDLR BACE_HUMAN 115 3 -
RQLFSTYRDLR Q8IYC8_HUMAN 115 3 -
RQRSSTYRDLR BACE1_CAVPO 112 3 -
RQHSRTYRDVR Q0P4T5_XENTR 116 3 -
RSLSSSYRDLG Q6NZT7_DANRE 120 3 -

Motif 3 width=21
Element Seqn Id St Int Rpt
SLQLCGAGFPLNQTEALASVG BACE_MOUSE 212 86 -
SLQLCGAGFPLNQTEALASVG Q8C7R1_MOUSE 212 86 -
SLQLCGAGFPLNQTEALASVG Q8C4F4_MOUSE 212 86 -
SLQLCGAGFPLNQTEALASVG Q8BQY4_MOUSE 212 86 -
SLQLCGAGFPLNQTEALASVG BACE_RAT 212 86 -
SLQLCGAGFPLNQSEALASVG BACE1_BOVIN 212 86 -
SLQLCGAGFPLNQSEVLASVG A0M8W7_HUMAN 212 86 -
SLQLCGAGFPLNQSEVLASVG BACE_HUMAN 212 86 -
SLQLCGAGFPLNQSEVLASVG Q8IYC8_HUMAN 212 86 -
IARLCGAGFPLNQSEAVASVG BACE1_CAVPO 184 61 -
SLQLCGTGFHFNESDTSASVG Q0P4T5_XENTR 213 86 -
SLQLCGAGYNHNYSTGSSSTV Q6NZT7_DANRE 217 86 -

Motif 4 width=15
Element Seqn Id St Int Rpt
TILPQQYLRPVEDVA BACE_MOUSE 360 127 -
TILPQQYLRPVEDVA Q8C7R1_MOUSE 360 127 -
TILPQQYLRPVEDVA Q8C4F4_MOUSE 326 93 -
TILPQQYLRPVEDVA Q8BQY4_MOUSE 360 127 -
TILPQQYLRPVEDVA BACE_RAT 360 127 -
TILPQQYLRPVEDVA BACE1_BOVIN 360 127 -
TILPQQYLRPVEDVA A0M8W7_HUMAN 360 127 -
TILPQQYLRPVEDVA BACE_HUMAN 360 127 -
TILPQQYLRPVEDVA Q8IYC8_HUMAN 360 127 -
TILPQQYLRPVEDVA BACE1_CAVPO 332 127 -
TILPQQYLRPVEDIA Q0P4T5_XENTR 361 127 -
SILPQQYLRPVEDVA Q6NZT7_DANRE 366 128 -

Motif 5 width=13
Element Seqn Id St Int Rpt
FAVSACHVHDEFR BACE_MOUSE 415 40 -
FAVSACHVHDEFR Q8C7R1_MOUSE 415 40 -
FAVSACHVHDEFR Q8C4F4_MOUSE 381 40 -
FAVSACHVHDEFR Q8BQY4_MOUSE 415 40 -
FAVSACHVHDEFR BACE_RAT 415 40 -
FAVSACHVHDEFR BACE1_BOVIN 415 40 -
FAVSACHVHDEFR A0M8W7_HUMAN 415 40 -
FAVSACHVHDEFR BACE_HUMAN 415 40 -
FAVSACHVHDEFR Q8IYC8_HUMAN 415 40 -
FAVSACHVHDEFR BACE1_CAVPO 387 40 -
FAVSTCHVHDYFR Q0P4T5_XENTR 416 40 -
FAVSTCHVHDEFR Q6NZT7_DANRE 421 40 -

Motif 6 width=20
Element Seqn Id St Int Rpt
PFVTADMEDCGYNIPQTDES BACE_MOUSE 434 6 -
PFVTADMEDCGYNIPQTDES Q8C7R1_MOUSE 434 6 -
PFVTADMEDCGYNIPQTDES Q8C4F4_MOUSE 400 6 -
PFVTADMEDCGYNIPQTDES Q8BQY4_MOUSE 434 6 -
PFVTADMEDCGYNIPQTDES BACE_RAT 434 6 -
PFVTPDMEDCGYNIPQTDES BACE1_BOVIN 434 6 -
PFVTLDMEDCGYNIPQTDES A0M8W7_HUMAN 434 6 -
PFVTLDMEDCGYNIPQTDES BACE_HUMAN 434 6 -
PFVTLDMEDCGYNIPQTDES Q8IYC8_HUMAN 434 6 -
PFVTPDMEDCGYNIPQTDES BACE1_CAVPO 406 6 -
PFFASDLEDCGYNTPQLDES Q0P4T5_XENTR 435 6 -
PFHGLDLEDCGYNVPQTDES Q6NZT7_DANRE 440 6 -

Motif 7 width=21
Element Seqn Id St Int Rpt
LMTIAYVMAAICALFMLPLCL BACE_MOUSE 455 1 -
LMTIAYVMAAICALFMLPLCL Q8C7R1_MOUSE 455 1 -
LMTIAYVMAAICALFMLPLCL Q8C4F4_MOUSE 421 1 -
LMTIAYVMAAICALFMLPLCL Q8BQY4_MOUSE 455 1 -
LMTIAYVMAAICALFMLPLCL BACE_RAT 455 1 -
LMTIAYVMAAICALFMLPLCL BACE1_BOVIN 455 1 -
LMTIAYVMAAICALFMLPLCL A0M8W7_HUMAN 455 1 -
LMTIAYVMAAICALFMLPLCL BACE_HUMAN 455 1 -
LMTIAYVMAAICALFMLPLCL Q8IYC8_HUMAN 455 1 -
LMTIAYVMAAICALFMLPLCL BACE1_CAVPO 427 1 -
LMTTAYVMAGVCALFMLPLCL Q0P4T5_XENTR 456 1 -
LMTIAYIMAGICALFMLPLCV Q6NZT7_DANRE 461 1 -