UniProtKB/Swiss-Prot Q99497: Variant p.Leu166Pro

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 166 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 Proline (P) at position 166 (L166P, p.Leu166Pro). 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: Similar physico-chemical property. Both residues are medium size and hydrophobic. The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: -3 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 PARK7; strongly decreases enzymatic activity; reduces protein stability and leads to increased degradation; ubiquitinated by PRKN leading to its recognition by HDAC6 and targeting to aggresome where is degraded; interferes with homodimerization; abolishes interaction with PIAS2; reduced localization in lipid rafts; almost abolished detoxification activity on methylglyocal-adducted CoA. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs28938172 [ dbSNP | Ensembl ]

Sequence information

Variant position: 166 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: 189 The length of the canonical sequence.
Location on the sequence: VEKDGLILTSRGPGTSFEFA L AIVEALNGKEVAAQVKAPLV 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
Modified residue	148 – 148	N6-acetyllysine
Modified residue	182 – 182	N6-succinyllysine
Mutagenesis	179 – 179	A -> T. No effect on detoxification activity on methylglyocal-adducted CoA.
Helix	161 – 173

Literature citations

L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system.
Miller D.W.; Ahmad R.; Hague S.; Baptista M.J.; Canet-Aviles R.; McLendon C.; Carter D.M.; Zhu P.-P.; Stadler J.; Chandran J.; Klinefelter G.R.; Blackstone C.; Cookson M.R.;
J. Biol. Chem. 278:36588-36595(2003)
Cited for: DEGRADATION BY THE PROTEASOME; SUBCELLULAR LOCATION; INTERACTION WITH PIAS2; HOMODIMERIZATION; MUTAGENESIS OF LYS-130; CHARACTERIZATION OF VARIANT PARK7 PRO-166; A missense mutation (L166P) in DJ-1, linked to familial Parkinson's disease, confers reduced protein stability and impairs homo-oligomerization.
Moore D.J.; Zhang L.; Dawson T.M.; Dawson V.L.;
J. Neurochem. 87:1558-1567(2003)
Cited for: DEGRADATION BY THE PROTEASOME; CHARACTERIZATION OF VARIANTS PARK7 ILE-26 AND PRO-166; Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation.
Xiong H.; Wang D.; Chen L.; Choo Y.S.; Ma H.; Tang C.; Xia K.; Jiang W.; Ronai Z.; Zhuang X.; Zhang Z.;
J. Clin. Invest. 119:650-660(2009)
Cited for: FUNCTION; COMPONENT OF A COMPLEX COMPOSED OF PRKN; PARK7 AND PINK1; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT PARK7 PRO-166; Human DJ-1 and its homologs are novel glyoxalases.
Lee J.Y.; Song J.; Kwon K.; Jang S.; Kim C.; Baek K.; Kim J.; Park C.;
Hum. Mol. Genet. 21:3215-3225(2012)
Cited for: FUNCTION; CAUTION; MUTAGENESIS OF GLU-18; CYS-106 AND HIS-126; CHARACTERIZATION OF VARIANT PARK7 PRO-166; DJ-1 associates with lipid rafts by palmitoylation and regulates lipid rafts-dependent endocytosis in astrocytes.
Kim K.S.; Kim J.S.; Park J.Y.; Suh Y.H.; Jou I.; Joe E.H.; Park S.M.;
Hum. Mol. Genet. 22:4805-4817(2013)
Cited for: FUNCTION; PALMITOYLATION AT CYS-46; CYS-53 AND CYS-106; SUBCELLULAR LOCATION; MUTAGENESIS OF CYS-46 AND CYS-106; CHARACTERIZATION OF VARIANT PARK7 PRO-166; Parkinson's disease-related DJ-1 functions in thiol quality control against aldehyde attack in vitro.
Matsuda N.; Kimura M.; Queliconi B.B.; Kojima W.; Mishima M.; Takagi K.; Koyano F.; Yamano K.; Mizushima T.; Ito Y.; Tanaka K.;
Sci. Rep. 7:12816-12816(2017)
Cited for: FUNCTION; MUTAGENESIS OF LEU-10; GLU-18; CYS-106 AND ALA-179; CHARACTERIZATION OF VARIANTS PARK7 ILE-26; ASP-64; THR-104; ALA-149; LYS-163 AND PRO-166; CHARACTERIZATION OF VARIANT SER-39; Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism.
Bonifati V.; Rizzu P.; van Baren M.J.; Schaap O.; Breedveld G.J.; Krieger E.; Dekker M.C.J.; Squitieri F.; Ibanez P.; Joosse M.; van Dongen J.W.; Vanacore N.; van Swieten J.C.; Brice A.; Meco G.; van Duijn C.M.; Oostra B.A.; Heutink P.;
Science 299:256-259(2003)
Cited for: VARIANT PARK7 PRO-166; SUBCELLULAR LOCATION; Differential effects of Parkinson's disease-associated mutations on stability and folding of DJ-1.
Goerner K.; Holtorf E.; Odoy S.; Nuscher B.; Yamamoto A.; Regula J.T.; Beyer K.; Haass C.; Kahle P.J.;
J. Biol. Chem. 279:6943-6951(2004)
Cited for: CHARACTERIZATION OF VARIANTS PARK7 ASP-64 AND PRO-166; Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6.
Olzmann J.A.; Li L.; Chudaev M.V.; Chen J.; Perez F.A.; Palmiter R.D.; Chin L.S.;
J. Cell Biol. 178:1025-1038(2007)
Cited for: CHARACTERIZATION OF VARIANT PARK7 PRO-166;