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PR01073

Identifier
PRESENILIN1  [View Relations]  [View Alignment]  
Accession
PR01073
No. of Motifs
4
Creation Date
01-MAR-1999  (UPDATE 07-JUN-1999)
Title
Presenilin 1 signature
Database References
PRINTS; PR01072 PRESENILIN
PRODOM; PD011526; PD013936
INTERPRO; IPR002031
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. 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).

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. 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. 
 
Presenilin 1 has been shown to be phosphorylated by protein kinase C, and is
endogenously cleaved into 28kD N-terminal and 19kD C-terminal fragments.
Consequently, little of the uncleaved peptide is detectable in vivo. PS1
gene mutations are thought to account for the majority of early-onset
familial Alzheimer's disease cases. To date, 45 different mutations have
been identified in PS1, all but one of which result in a single amino change
in the presenilin 1 molecule. Affected residues always occur in regions of
the sequence that are conserved between presenilins 1 and 2, and the C.elegans
homologue, sel-12 [3]. 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. 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.
 
PRESENILIN1 is a 4-element fingerprint that provides a signature for type 1 
presenilins. The fingerprint was derived from an initial alignment of 3 
sequences: the motifs were drawn from conserved regions spanning the
N-terminal two thirds of the alignment, focusing on those sections that 
characterise presenilin 1 but distinguish it from other isoforms - motifs 
1-3 reside within the putative cytoplasmic N-terminus; and motif 4 lies at
the N-terminus of the large putative cytoplasmic loop, close to the site of
normal proteolytic cleavage. Two iterations on OWL31.1 were required to
reach convergence, at which point a true set comprising 8 sequences was
identified.  A single partial match was also found, a presenilin-alpha
protein from Xenopus laevis that matches motifs 2 and 3.
 
An update on SPTR37_9f identified a true set of 5 sequences.
Summary Information
5 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
45555
30000
20000
1234
True Positives
P79802        P97529        P97887        PSN1_HUMAN    
PSN1_MOUSE
Sequence Titles
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).
Scan History
OWL31_1    2  200  NSINGLE    
SPTR37_9f 2 6 NSINGLE
Initial Motifs
Motif 1  width=21
Element Seqn Id St Int Rpt
MTELPAPLSYFQNAQMSEDNH PSN1_HUMAN 1 1 -
MTELPAPLSYFQNAQMSEDNH JC5080 1 1 -
MTEIPAPLSYFQNAQMSEDSH D82363 1 1 -

Motif 2 width=15
Element Seqn Id St Int Rpt
LGHPEPLSNGRPQGN PSN1_HUMAN 44 22 -
LGNPEPLSNGRPQGN JC5080 44 22 -
LDNPESISNGRPQSN D82363 43 21 -

Motif 3 width=12
Element Seqn Id St Int Rpt
QVIEQDEEEDEE D82363 61 3 -
QVVEQDEEEDEE PSN1_HUMAN 61 2 -
PVVERDEEEDEE JC5080 61 2 -

Motif 4 width=13
Element Seqn Id St Int Rpt
EGDPEAQRRVSKN PSN1_HUMAN 300 227 -
EGDPEAQRRVPKN D82363 300 227 -
EGDPEAQRRVSKN JC5080 300 227 -
Final Motifs
Motif 1  width=21
Element Seqn Id St Int Rpt
MTEIPAPLSYFQNAQMSEDSH PSN1_MOUSE 1 1 -
MTEIPAPLSYFQNAQMSEDSH P97529 1 1 -
MTEIPAPLSYFQNAQMSEDSH P97887 1 1 -
MTELPAPLSYFQNAQMSEDNH PSN1_HUMAN 1 1 -
MTELPAPLSYFQNAQMSEDNH P79802 1 1 -

Motif 2 width=15
Element Seqn Id St Int Rpt
LDNPEPISNGRPQSN PSN1_MOUSE 44 22 -
LDNPESISNGRPQSN P97529 43 21 -
LDNPESISNGRPQSN P97887 43 21 -
LGHPEPLSNGRPQGN PSN1_HUMAN 44 22 -
LGNPEPLSNGRPQGN P79802 44 22 -

Motif 3 width=12
Element Seqn Id St Int Rpt
QVVEQDEEEDEE PSN1_MOUSE 61 2 -
QVIEQDEEEDEE P97529 61 3 -
QVIEQDEEEDEE P97887 61 3 -
QVVEQDEEEDEE PSN1_HUMAN 61 2 -
PVVERDEEEDEE P79802 61 2 -

Motif 4 width=13
Element Seqn Id St Int Rpt
EGDPEAQRRVPKN PSN1_MOUSE 300 227 -
EGDPEAQRRVPKN P97529 300 227 -
EGDPEAQRRVPKN P97887 300 227 -
EGDPEAQRRVSKN PSN1_HUMAN 300 227 -
EGDPEAQRRVSKN P79802 300 227 -