UniProtKB/SwissProt variant VAR

Variant information

Variant position:

93

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

Type of variant:

LP/P [Disclaimer]

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 Isoleucine (I) to Methionine (M) at position 93 (I93M, p.Ile93Met).

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:

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

Variant description:

In PARK5; impaired enzymatic hydrolase activity; has about a 50% reduction in catalytic activity compared to wild-type protein.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs121917767 [ dbSNP | Ensembl ]

Sequence information

Variant position:

93

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

Protein sequence length:

223

The length of the canonical sequence.

Location on the sequence:

QEVSPKVYFMKQTIGNSCGT I GLIHAVANNQDKLGFEDGSV

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.

Residue conservation:

The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         QEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLGFEDGSV

Mouse                         QEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLEFEDGSV

Rat                           QEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLEFEDGSV

Pig                           QEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLEFEDGSV

Bovine                        QEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLEFEDGSV

Horse                         QEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLEFEDGSV

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	1 – 220	Ubiquitin carboxyl-terminal hydrolase isozyme L1
Active site	90 – 90	Nucleophile
Mutagenesis	73 – 73	Q -> R. No effect on enzymatic parameters.
Mutagenesis	90 – 90	C -> S. Abolishes enzymatic activity.
Mutagenesis	97 – 97	H -> QN. 2-fold increase in affinity for ubiquitin ethyl ester, slight reduction in enzymatic activity.
Helix	90 – 100

Literature citations

The ubiquitin pathway in Parkinson's disease.
Leroy E.; Boyer R.; Auburger G.; Leube B.; Ulm G.; Mezey E.; Harta G.; Brownstein M.J.; Jonnalagada S.; Chernova T.; Dehejia A.; Lavedan C.; Gasser T.; Steinbach P.J.; Wilkinson K.D.; Polymeropoulos M.H.;
Nature 395:451-452(1998)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-223; FUNCTION; CATALYTIC ACTIVITY; BIOPHYSICOCHEMICAL PROPERTIES; VARIANT PARK5 MET-93; CHARACTERIZATION OF VARIANT PARK5 MET-93;

The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.
Liu Y.; Fallon L.; Lashuel H.A.; Liu Z.; Lansbury P.T. Jr.;
Cell 111:209-218(2002)
Cited for: FUNCTION; CATALYTIC ACTIVITY; CHARACTERIZATION OF VARIANT PARK5 MET-93; CHARACTERIZATION OF VARIANT TYR-18;

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.
Bilguvar K.; Tyagi N.K.; Ozkara C.; Tuysuz B.; Bakircioglu M.; Choi M.; Delil S.; Caglayan A.O.; Baranoski J.F.; Erturk O.; Yalcinkaya C.; Karacorlu M.; Dincer A.; Johnson M.H.; Mane S.; Chandra S.S.; Louvi A.; Boggon T.J.; Lifton R.P.; Horwich A.L.; Gunel M.;
Proc. Natl. Acad. Sci. U.S.A. 110:3489-3494(2013)
Cited for: FUNCTION; CATALYTIC ACTIVITY; VARIANTS SPG79 ALA-7 AND MET-93; CHARACTERIZATION OF VARIANT SPG79 ALA-7; MUTAGENESIS OF CYS-90;

Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation.
Boudreaux D.A.; Maiti T.K.; Davies C.W.; Das C.;
Proc. Natl. Acad. Sci. U.S.A. 107:9117-9122(2010)
Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF VARIANTS TYR-18 AND MET-93 IN COMPLEX WITH UBIQUITIN; CATALYTIC ACTIVITY; ACTIVE SITE; MUTAGENESIS OF CYS-90 AND PHE-204;

Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants.
Nishikawa K.; Li H.; Kawamura R.; Osaka H.; Wang Y.-L.; Hara Y.; Hirokawa T.; Manago Y.; Amano T.; Noda M.; Aoki S.; Wada K.;
Biochem. Biophys. Res. Commun. 304:176-183(2003)
Cited for: CHARACTERIZATION OF VARIANT PARK5 MET-93; CHARACTERIZATION OF VARIANT TYR-18; MUTAGENESIS OF CYS-90; CATALYTIC ACTIVITY; BIOPHYSICOCHEMICAL PROPERTIES;

The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease.
Harhangi B.S.; Farrer M.J.; Lincoln S.; Bonifati V.; Meco G.; De Michele G.; Brice A.; Durr A.; Martinez M.; Gasser T.; Bereznai B.; Vaughan J.R.; Wood N.W.; Hardy J.; Oostra B.A.; Breteler M.M.;
Neurosci. Lett. 270:1-4(1999)
Cited for: VARIANT MET-93;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P09936: Variant p.Ile93Met