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UniProtKB/Swiss-Prot P49768: Variant p.Pro436Ser

Presenilin-1
Gene: PSEN1
Variant information

Variant position:  436
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Proline (P) to Serine (S) at position 436 (P436S, p.Pro436Ser).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and hydrophobic (P) to small size and polar (S)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -1
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481, ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11561050, ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851, ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344, ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188, ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849, ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340, ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735, ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784, ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383, ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661, ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781, ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961, ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897, ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164, ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783, ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983, ECO:0000269|PubMed:30200536, ECO:0000269|PubMed:7550356, ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:8837617, ECO:0000269|PubMed:9172170, ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, ECO:0000269|Ref.92}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In AD3; partially abolishes gamma-secretase activity; results in altered amyloid-beta production and increased amyloid-beta 42/amyloid-beta 40 ratio.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  436
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  467
The length of the canonical sequence.

Location on the sequence:   IGLCLTLLLLAIFKKALPAL  P ISITFGLVFYFATDYLVQPF
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 299 – 467 Presenilin-1 CTF subunit
Chain 346 – 467 Presenilin-1 CTF12
Transmembrane 433 – 453 Helical
Region 322 – 450 Required for interaction with CTNNB1
Alternative sequence 185 – 467 Missing. In isoform 4.
Alternative sequence 319 – 467 STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPMAPRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI. In isoform 3 and isoform 5.
Mutagenesis 420 – 420 L -> R. Decreased protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis 424 – 424 L -> V. Increases protease activity with APP.
Mutagenesis 432 – 432 L -> P. Loss of NOTCH1 and APP C83 cleavage.
Mutagenesis 433 – 433 P -> A. No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Slightly increased amyloid-beta protein 42/40 ratio.
Mutagenesis 433 – 433 P -> DFLNV. No endoproteolytic cleavage; no APP, nor NOTCH1 processing. No detectable amyloid-beta.
Mutagenesis 433 – 433 P -> G. Very little endoproteolysis. Little APP processing. No NOTCH1 processing. Very low levels amyloid-beta protein 40 and no detectable amyloid-beta protein 42.
Mutagenesis 434 – 434 A -> C. Some loss of endoproteolytic cleavage. Some loss of APP and NOTCH1 processing. 6 to 13-fold increase in amyloid-beta protein 42/40 ratio.
Mutagenesis 434 – 434 A -> DILV. No endoproteolytic cleavage. No APP nor NOTCH1 processing. No detectable amyloid-beta.
Mutagenesis 434 – 434 A -> G. No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Reduced amyloid-beta protein 42/40 ratio.
Mutagenesis 435 – 435 L -> A. No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Greatly reduced amyloid-beta protein 42/40 ratio.
Mutagenesis 435 – 435 L -> G. Greatly reduced endoproteolytic cleavage. Very little APP and NOTCH1 processing. Very low levels of amyloid-beta protein 40 and no detectable amyloid-beta protein 42.
Mutagenesis 435 – 435 L -> I. No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing.
Mutagenesis 435 – 435 L -> R. No endoproteolytic cleavage; no APP, nor NOTCH1 processing. No detectable amyloid-beta.
Mutagenesis 435 – 435 L -> V. No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Some increase in amyloid-beta protein 42/40 ratio.
Mutagenesis 437 – 437 I -> V. Decreased protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.


Literature citations

Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset Alzheimer's disease in the UK.
Palmer M.S.; Beck J.A.; Campbell T.A.; Humphries C.B.; Roques P.K.; Fox N.C.; Harvey R.; Rossor M.N.; Collinge J.;
Hum. Mutat. 13:256-256(1999)
Cited for: VARIANTS AD3 PHE-143 AND SER-436;

A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity.
Heilig E.A.; Xia W.; Shen J.; Kelleher R.J. III;
J. Biol. Chem. 285:22350-22359(2010)
Cited for: VARIANT AD3 PHE-435; CHARACTERIZATION OF VARIANTS AD3 PHE-435; GLN-436 AND SER-436; MUTAGENESIS OF PRO-433 AND LEU-435; FUNCTION;

Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase.
Sun L.; Zhou R.; Yang G.; Shi Y.;
Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017)
Cited for: CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89; SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120; ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154; ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174; LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209; LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235; PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262; ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275; ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378; VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405; THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439; CHARACTERIZATION OF VARIANT CMD1U GLY-333; MUTAGENESIS OF THR-99; PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143; LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214; LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248; TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365; ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.