UniProtKB/Swiss-Prot P49768: Variant p.Leu435Phe

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 435 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: LP/P [Disclaimer: Variants classification is intended for research purposes only, not for clinical and diagnostic use. The label disease variant is assigned according to literature reports on probable disease-association that can be based on theoretical reasons. This label must not be considered as a definitive proof for the pathogenic role of a variant.] 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 Leucine (L) to Phenylalanine (F) at position 435 (L435F, p.Leu435Phe). 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 (L) to large size and aromatic (F) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: 0 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; with unusual amyloid cotton wool plaques; almost abolishes gamma-secretase activity; no endoproteolytic cleavage; no APP nor NOTCH1 processing; no detectable amyloid-beta. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs63750001 [ dbSNP | Ensembl ]

Sequence information

Variant position: 435 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: LIGLCLTLLLLAIFKKALPA L PISITFGLVFYFATDYLVQP 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
Transmembrane	433 – 453	Helical
Region	322 – 450	Required for interaction with CTNNB1
Motif	433 – 435	PAL
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.
Beta strand	432 – 435

Literature citations

C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation.
Wang J.; Beher D.; Nyborg A.C.; Shearman M.S.; Golde T.E.; Goate A.;
J. Neurochem. 96:218-227(2006)
Cited for: FUNCTION OF PAL MOTIF; MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435; CHARACTERIZATION OF VARIANT AD3 PHE-435; 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; 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; Trans-dominant negative effects of pathogenic PSEN1 mutations on gamma-secretase activity and Abeta production.
Heilig E.A.; Gutti U.; Tai T.; Shen J.; Kelleher R.J. III;
J. Neurosci. 33:11606-11617(2013)
Cited for: CHARACTERIZATION OF VARIANTS AD3 PRO-166; ILE-278; ALA-384; VAL-392; TYR-410 AND PHE-435; 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;