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PR01074

Identifier
PRESENILIN2  [View Relations]  [View Alignment]  
Accession
PR01074
No. of Motifs
4
Creation Date
01-MAR-1999  (UPDATE 07-JUN-1999)
Title
Presenilin 2 signature
Database References
PRINTS; PR01072 PRESENILIN
PRODOM; PD013935; PD013937
INTERPRO; IPR001493
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. 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. 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 2 (unlike presenilin 1) has been found to have pro-apoptotic 
actions, which are enhanced by the mutations that have been characterised
in this protein; however, when compared to PS1 gene mutations, they are
thought to be responsible for only a small percentage of early-onset
familial Alzheimer's disease cases (ca. 1%) [3].
 
PRESENILIN2 is a 4-element fingerprint that provides a signature for type 2
presenilins. The fingerprint was derived from an initial alignment of 3
sequences: the motifs were drawn from conserved regions spanning virtually
the full alignment length, focusing on those sections that characterise
presenilin 2 but distinguish it from other isoforms - motifs 1 and 2 lie in
the putative N-terminal cytoplasmic region; and motifs 3 and 4 reside in the
putative cytoplasmic large hydrophilic loop. Two iterations on OWL31.1 were
required to reach convergence, at which point a true set comprising 8
sequences was identified.
 
An update on SPTR37_9f identified a true set of 6 sequences.
Summary Information
6 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
46666
30000
20000
1234
True Positives
O08947        O35546        O54977        O88777        
PSN2_HUMAN PSN2_MOUSE
Sequence Titles
O08947      PRESENILIN 2 (PS-2) - RATTUS NORVEGICUS (RAT). 
O35546 PRESENILIN 2 (PS-2) - RATTUS NORVEGICUS (RAT).
O54977 PRESENILIN 2 (PS-2) (ALG-3) (ALZHEIMER DISEASE 4 HOMOLOG) - MUS MUSCULUS (MOUSE).
O88777 PRESENILIN 2 (PS-2) - RATTUS NORVEGICUS (RAT).
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).
Scan History
OWL31_1    2  300  NSINGLE    
SPTR37_9f 2 7 NSINGLE
Initial Motifs
Motif 1  width=23
Element Seqn Id St Int Rpt
FMASDSEEEVCDERTSLMSAESP PSN2_HUMAN 4 4 -
FMASDSEEEVCDERTSLMSAESP PSN2_MOUSE 4 4 -
FMASDSEEEVCDERTSLMSAESP AB004454 4 4 -

Motif 2 width=12
Element Seqn Id St Int Rpt
GPEDGESTAQWR PSN2_MOUSE 37 10 -
GPEDGENTAQWR AB004454 37 10 -
GPEDGENTAQWR PSN2_HUMAN 37 10 -

Motif 3 width=19
Element Seqn Id St Int Rpt
KLDPSSQGALQLPYDPEME AB004454 306 257 -
KLDPSSQGALQLPYDPEME PSN2_MOUSE 306 257 -
KLDPSSQGALQLPYDPEME PSN2_HUMAN 306 257 -

Motif 4 width=17
Element Seqn Id St Int Rpt
SYDSFGEPSYPEVFEPP PSN2_HUMAN 327 2 -
SYDSFGEPSYPEAFEAP PSN2_MOUSE 327 2 -
SYDSFGEPSYPEAFEAP AB004454 327 2 -
Final Motifs
Motif 1  width=23
Element Seqn Id St Int Rpt
FMASDSEEEVCDERTSLMSAESP O08947 4 4 -
FMASDSEEEVCDERTSLMSAESP O35546 4 4 -
FMASDSEEEVCDERTSLMSAESP O54977 4 4 -
FMASDSEEEVCDERTSLMSAESP PSN2_MOUSE 4 4 -
FMATDSEEEVCDERTSLMSAESP O88777 4 4 -
FMASDSEEEVCDERTSLMSAESP PSN2_HUMAN 4 4 -

Motif 2 width=12
Element Seqn Id St Int Rpt
GPEDGENTAQWR O08947 37 10 -
GPEDGENTAQWR O35546 37 10 -
GPEDGESTAQWR O54977 37 10 -
GPEDGESTAQWR PSN2_MOUSE 37 10 -
GPEDGENTAQWR O88777 37 10 -
GPEDGENTAQWR PSN2_HUMAN 37 10 -

Motif 3 width=19
Element Seqn Id St Int Rpt
KLDPSSQGALQLPYDPEME O08947 306 257 -
KLDPSSQGALQLPYDPEME O35546 306 257 -
KLDPSSQGALQLPYDPEME O54977 306 257 -
KLDPSSQGALQLPYDPEME PSN2_MOUSE 306 257 -
KLDPSSQGALQLPYDPEME O88777 306 257 -
KLDPSSQGALQLPYDPEME PSN2_HUMAN 306 257 -

Motif 4 width=17
Element Seqn Id St Int Rpt
SYDSFGEPSYPEAFEAP O08947 327 2 -
SYDSFGEPSYPEAFEAP O35546 327 2 -
SYDSFGEPSYPEAFEAP O54977 326 1 -
SYDSFGEPSYPEAFEAP PSN2_MOUSE 327 2 -
SYDSFGEPSYPEAFEAP O88777 327 2 -
SYDSFGEPSYPEVFEPP PSN2_HUMAN 327 2 -