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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P49768: Variant p.Ser365Tyr

Presenilin-1
Gene: PSEN1
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Variant information Variant position: help 365 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help US The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change: help From Serine (S) to Tyrosine (Y) at position 365 (S365Y, p.Ser365Tyr). 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: help Change from small size and polar (S) to large size and aromatic (Y) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help -2 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

Variant description: help In AD3; uncertain significance. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 365 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 467 The length of the canonical sequence.
Location on the sequence: help DSHLGPHRSTPESRAAVQEL S SSILAGEDPEERGVKLGLGD 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: help 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
Topological domain 273 – 380 Cytoplasmic
Region 322 – 450 Required for interaction with CTNNB1
Active site 385 – 385
Modified residue 346 – 346 Phosphoserine; by PKC
Modified residue 367 – 367 Phosphoserine
Alternative sequence 185 – 467 Missing. In isoform 4.
Alternative sequence 319 – 467 STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPMAPRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI. In isoform 3 and isoform 5.
Alternative sequence 319 – 376 Missing. In isoform 6.
Mutagenesis 345 – 345 D -> N. Abolishes caspase cleavage.
Mutagenesis 346 – 346 S -> A. Abolishes PKC-mediated phosphorylation; no effect on PKA-mediated phosphorylation.
Mutagenesis 346 – 346 S -> E. Inhibits caspase-mediated cleavage. Modulates progression of apoptosis.
Mutagenesis 352 – 352 R -> C. Decreased protease activity with APP.
Mutagenesis 365 – 365 S -> A. Slightly increased protease activity with APP.
Mutagenesis 373 – 373 D -> N. No effect on caspase cleavage.
Mutagenesis 377 – 377 R -> W. Nearly abolishes protease activity with APP.
Mutagenesis 385 – 385 D -> A. Loss of endoproteolytic cleavage. Severe decrease of protease activity with APP. Reduces production of amyloid-beta. Loss of NOTCH1 cleavage. Disassembly of the N-cadherin/PS1 complex at the cell surface. Impairs CDH2 processing.
Mutagenesis 385 – 385 D -> E. Abolishes gamma-secretase activity. Reduces production of amyloid-beta in APP processing. Accumulation of full-length PS1. Loss of binding of transition state analog gamma-secretase inhibitor.
Mutagenesis 385 – 385 D -> N. No effect on caspase cleavage.
Helix 356 – 368



Literature citations
Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations.
Rogaeva E.A.; Fafel K.C.; Song Y.Q.; Medeiros H.; Sato C.; Liang Y.; Richard E.; Rogaev E.I.; Frommelt P.; Sadovnick A.D.; Meschino W.; Rockwood K.; Boss M.A.; Mayeux R.; St George-Hyslop P.;
Neurology 57:621-625(2001)
Cited for: VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146; VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178; ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235; PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418; GLU-431; PHE-435 AND VAL-439; VARIANT GLY-318;
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.