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PR01072

Identifier
PRESENILIN  [View Relations]  [View Alignment]  
Accession
PR01072
No. of Motifs
4
Creation Date
02-MAR-1999  (UPDATE 23-JUN-1999)
Title
Presenilin family signature
Database References
PRINTS; PR01073 PRESENILIN1; PR01074 PRESENILIN2; PR01075 PRESENILNSEL

PRODOM; PD00364; PD003731
INTERPRO; IPR001108
Literature References
1. MARTIN, G.M.
Introduction: genetic determinants of mid- and late-life dementias.
CELL.MOL.LIFE SCI. 54 895-896 (1998).
 
2. CRUTS, M. AND VAN BROECKHOVEN, C.
Presenilin mutations in Alzheimer's disease.
HUM.MUTAT. 11 183-190 (1998).
 
3. LEVITAN, D. AND GREENWALD, I.
Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis 
elegans S182 Alzheimer's disease gene.
NATURE 377 351-354 (1995).
 
4. KOVACS, D.M. AND TANZI, R.E.
Monogenic determinants of familial Alzheimer's disease: presenilin-1 
mutations.
CELL.MOL.LIFE SCI. 54 902-909 (1998).
 
5. RENBAUM, P. AND LEVY-LAHAD, E.
Monogenic determinants of familial Alzheimer's disease: presenilin-2 
mutations.
CELL.MOL.LIFE SCI. 54 910-919 (1998).

Documentation
Presenilins are polytopic transmembrane (TM) proteins, mutations in which 
are associated with the occurrence of early-onset familial Alzheimer's 
disease, a rare form of the disease that results from a single-gene
mutation [1,2]. While the aetiology of Alzheimer's disease is unresolved,
all forms are typified by a global cognitive decline and the occurrence of  
characteristic neuropathological changes. Invariably, post-mortem brains
from Alzheimer's patients contain abundant neurofibrillary tangles, together
with depositions of beta-amyloid protein as senile plaques.
 
The physiological functions of presenilins are unknown, but they may be 
related to developmental signalling, apoptotic signal transduction, or
processing of selected proteins, such as the beta-amyloid precursor protein
(beta-APP). That presenilin homologues have been identified in species that
do not have an Alzhemier's disease correlate suggests that they may have 
functions unrelated to the disease, homologues having been identified in
mouse, Drosophila and C.elegans [3]. In the latter, the sel-12 protein (a 
worm homologue of the mammalian presenilins) has been demonstrated to
facilitate the function of the Notch receptor, which plays a role in cell-
cell signalling during cell differentiation in development. Intriguingly,
presenilin 1 is able to restore function in a C.elegans mutant lacking
sel-12, suggesting presenilin may also be involved in cell-cell signalling
in higher species.
 
In humans, there are two presenilin genes (PS1 and PS2), encoding proteins
of 467 and 448 amino acids respectively. They share 67% amino acid identity,
the greatest divergence between the two falling in the N-terminus and in the
large hydrophilic loop towards the C-terminal part of each molecule. Six to
nine TM domains are predicted for each, and biochemical analysis has
demonstrated that their C-termini are cytoplasmic; but the orientation of
their N-termini and large hydrophilic loops remains to be resolved. They
are expressed in almost all tissues, including the brain and, at a cellular
level, they have been localised to the nuclear envelope, endoplasmic
reticulum and Golgi apparatus. 
 
To date, 45 different gene mutations have been identified in PS1, all but one
of which result in a single amino change in the presenilin 1 molecule [4].
Affected residues always occur in regions of the sequence that are conserved
between presenilins 1 and 2, and the C.elegans  homologue, sel-12. The
mutations are thought to be responsible for ~50% of cases of early-onset
familial Alzheimer's disease, in contrast, less than 1% resulting from
mutations in PS2 [5]. How the mutations trigger disease is unknown, but
one biochemical effect consistently associated with them is an alteration in
the proteolytic cleavage of beta-APP such that there is overproduction of
long-tailed beta-amyloid peptide derivatives.
 
PRESENILIN is a 4-element fingerprint that provides a signature for the
presenilin family. The fingerprint was derived from an initial alignment of
6 sequences: the motifs were drawn from conserved regions spanning the
N-terminal two thirds of the alignment - motif 1 lies in putative TM domain
1; motif 2 lies in TM domain 6; motif 3 encodes the short loop connecting
the TM domains 6 and 7; and motif 4 lies within TM domain 7. Two iterations
on OWL31.1 were required to reach convergence, at which point a true set
comprising 25 sequences was identified.
 
An update on SPTR37_9f identified a true set of 19 sequences, and 5
partial matches.
Summary Information
  19 codes involving  4 elements
1 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
419191919
31110
20000
1234
True Positives
O02100        O02194        O02395        O08947        
O12976 O12977 O35546 O54977
O76802 O88777 P79802 P97529
P97887 PSN1_HUMAN PSN1_MOUSE PSN2_HUMAN
PSN2_MOUSE Q20076 SE12_CAEEL
True Positive Partials
Codes involving 3 elements
O64668
Sequence Titles
O02100      INTEGRAL MEMBRANE PROTEIN HOP-1 - CAENORHABDITIS ELEGANS. 
O02194 PRESENILIN HOMOLOG (DPS) (DMPS) - DROSOPHILA MELANOGASTER (FRUIT FLY).
O02395 PRESENILIN HOMOLOG (DPS) (DMPS) - DROSOPHILA MELANOGASTER (FRUIT FLY).
O08947 PRESENILIN 2 (PS-2) - RATTUS NORVEGICUS (RAT).
O12976 PRESENILIN ALPHA - XENOPUS LAEVIS (AFRICAN CLAWED FROG).
O12977 PRESENILIN BETA - XENOPUS LAEVIS (AFRICAN CLAWED FROG).
O35546 PRESENILIN 2 (PS-2) - RATTUS NORVEGICUS (RAT).
O54977 PRESENILIN 2 (PS-2) (ALG-3) (ALZHEIMER DISEASE 4 HOMOLOG) - MUS MUSCULUS (MOUSE).
O76802 PRESENILIN HOMOLOG (DPS) (DMPS) - DROSOPHILA MELANOGASTER (FRUIT FLY).
O88777 PRESENILIN 2 (PS-2) - RATTUS NORVEGICUS (RAT).
P79802 PRESENILIN 1 (PS-1) - MICROCEBUS MURINUS (LESSER MOUSE LEMUR).
P97529 PRESENILIN 1 (PS-1) (S182 PROTEIN) - RATTUS NORVEGICUS (RAT).
P97887 PRESENILIN 1 (PS-1) (S182 PROTEIN) - RATTUS NORVEGICUS (RAT).
PSN1_HUMAN PRESENILIN 1 (PS-1) (S182 PROTEIN) - HOMO SAPIENS (HUMAN).
PSN1_MOUSE PRESENILIN 1 (PS-1) (S182 PROTEIN) - MUS MUSCULUS (MOUSE).
PSN2_HUMAN PRESENILIN 2 (PS-2) (STM-2) (E5-1) (AD3LP) (AD5) - HOMO SAPIENS (HUMAN).
PSN2_MOUSE PRESENILIN 2 (PS-2) (ALG-3) (ALZHEIMER DISEASE 4 HOMOLOG) - MUS MUSCULUS (MOUSE).
Q20076 HYPOTHETICAL 94.6 KD PROTEIN F35H12.3 IN CHROMOSOME X - CAENORHABDITIS ELEGANS.
SE12_CAEEL INTEGRAL MEMBRANE PROTEIN SEL-12 - CAENORHABDITIS ELEGANS.

O64668 PRESENILIN HOMOLOG - ARABIDOPSIS THALIANA (MOUSE-EAR CRESS).
Scan History
OWL31_1    2  150  NSINGLE    
SPTR37_9f 1 300 NSINGLE
Initial Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
FVPVTLCMIVV AB004454 92 92 -
FVPVTLCMVVV D82363 86 86 -
FVPVTLCMVVV JC5080 86 86 -
FVPVTLCMVVV PSN1_HUMAN 86 86 -
FVPVTLCMIVV PSN2_MOUSE 92 92 -
FVPVTLCMIVV PSN2_HUMAN 92 92 -

Motif 2 width=8
Element Seqn Id St Int Rpt
YLPEWTAW JC5080 240 143 -
YLPEWTAW PSN1_HUMAN 240 143 -
YLPEWSAW PSN2_MOUSE 246 143 -
YLPEWSAW PSN2_HUMAN 246 143 -
YLPEWSAW AB004454 246 143 -
YLPEWTAW D82363 240 143 -

Motif 3 width=18
Element Seqn Id St Int Rpt
DLVAVLCPKGPLRMLVET PSN1_HUMAN 257 9 -
DLVAVLCPKGPLRMLVET D82363 257 9 -
DLVAVLCPKGPLRMLVET JC5080 257 9 -
DLVAVLCPKGPLRMLVET PSN2_MOUSE 263 9 -
DLVAVLCPKGPLRMLVET PSN2_HUMAN 263 9 -
DLVAVLCPKGPLRMLVET AB004454 263 9 -

Motif 4 width=8
Element Seqn Id St Int Rpt
FPALIYSS JC5080 283 8 -
FPALIYSS PSN2_MOUSE 289 8 -
FPALIYSS PSN2_HUMAN 289 8 -
FPALIYSS AB004454 289 8 -
FPALIYSS D82363 283 8 -
FPALIYSS PSN1_HUMAN 283 8 -
Final Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
FVPVTLCMVVV P79802 86 86 -
FVPVTLCMVVV PSN1_MOUSE 86 86 -
FVPVTLCMVVV PSN1_HUMAN 86 86 -
FVPVTLCMVVV P97887 86 86 -
FVPVTLCMVVV P97529 86 86 -
FVPVTLCMIVV PSN2_MOUSE 92 92 -
FVPVTLCMIVV PSN2_HUMAN 92 92 -
FVPVTLCMIVV O88777 92 92 -
FVPVTLCMIVV O54977 92 92 -
FVPVTLCMIVV O35546 92 92 -
FVPVTLCMIVV O08947 92 92 -
FVPVTLCMVVV O12977 95 95 -
FVPVTLCMVVV O12976 52 52 -
FVPVSLCMLVV O76802 108 108 -
FVPVSLCMLVV O02395 108 108 -
FVPVSLCMLVV O02194 108 108 -
FVPVSLCMALV Q20076 54 54 -
FVPVSLCMALV SE12_CAEEL 54 54 -
LYPVAICMLFV O02100 17 17 -

Motif 2 width=8
Element Seqn Id St Int Rpt
YLPEWTAW P79802 240 143 -
YLPEWTAW PSN1_MOUSE 240 143 -
YLPEWTAW PSN1_HUMAN 240 143 -
YLPEWTAW P97887 240 143 -
YLPEWTAW P97529 240 143 -
YLPEWSAW PSN2_MOUSE 246 143 -
YLPEWSAW PSN2_HUMAN 246 143 -
YLPEWSAW O88777 246 143 -
YLPEWSAW O54977 246 143 -
YLPEWSAW O35546 246 143 -
YLPEWSAW O08947 246 143 -
YLPEWSAW O12977 249 143 -
YLPEWTTW O12976 206 143 -
YLPEWTAW O76802 262 143 -
YLPEWTAW O02395 262 143 -
YLPEWTAW O02194 262 143 -
YLPEWTVW Q20076 209 144 -
YLPEWTVW SE12_CAEEL 209 144 -
ILPDWTVW O02100 165 137 -

Motif 3 width=18
Element Seqn Id St Int Rpt
DLVAVLCPKGPLRMLVET P79802 257 9 -
DLVAVLCPKGPLRMLVET PSN1_MOUSE 257 9 -
DLVAVLCPKGPLRMLVET PSN1_HUMAN 257 9 -
DLVAVLCPKGPLRMLVET P97887 257 9 -
DLVAVLCPKGPLRMLVET P97529 257 9 -
DLVAVLCPKGPLRMLVET PSN2_MOUSE 263 9 -
DLVAVLCPKGPLRMLVET PSN2_HUMAN 263 9 -
DLVAVLCPKGPLRMLVET O88777 263 9 -
DLVAVLCPKGPLRMLVET O54977 263 9 -
DLVAVLCPKGPLRMLVET O35546 263 9 -
DLVAVLCPKGPLRMLVET O08947 263 9 -
DLLAVLCPKGPLRMLVET O12977 266 9 -
DLVAVLSPKGPLRMLVET O12976 223 9 -
DLIAVLSPRGPLRILVET O76802 279 9 -
DLIAVLSPRGPLRILVET O02395 279 9 -
DLIAVLSPRGPLRILVET O02194 279 9 -
DLVAVLTPKGPLRYLVET Q20076 226 9 -
DLVAVLTPKGPLRYLVET SE12_CAEEL 226 9 -
DIVAVLTPCGPLKMLVET O02100 182 9 -

Motif 4 width=8
Element Seqn Id St Int Rpt
FPALIYSS P79802 283 8 -
FPALIYSS PSN1_MOUSE 283 8 -
FPALIYSS PSN1_HUMAN 283 8 -
FPALIYSS P97887 283 8 -
FPALIYSS P97529 283 8 -
FPALIYSS PSN2_MOUSE 289 8 -
FPALIYSS PSN2_HUMAN 289 8 -
FPALIYSS O88777 289 8 -
FPALIYSS O54977 289 8 -
FPALIYSS O35546 289 8 -
FPALIYSS O08947 289 8 -
FPALIYSS O12977 292 8 -
FPALIYSS O12976 249 8 -
FPALIYSS O76802 305 8 -
FPALIYSS O02395 305 8 -
FPALIYSS O02194 305 8 -
FPALIYSS Q20076 252 8 -
FPALIYSS SE12_CAEEL 252 8 -
FPAILYNS O02100 208 8 -