UniProtKB/Swiss-Prot P49768: Variant p.Ser365Tyr

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 365 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: 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: 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: 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: -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: In AD3; uncertain significance. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs63750941 [ dbSNP | Ensembl ]

Sequence information

Variant position: 365 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: 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: 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.

Type	Positions	Description
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;