Home  |  Contact

UniProtKB/Swiss-Prot O60260: Variant p.Arg42Pro

E3 ubiquitin-protein ligase parkin
Gene: PRKN
Variant information

Variant position:  42
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Arginine (R) to Proline (P) at position 42 (R42P, p.Arg42Pro).
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 large size and basic (R) to medium size and hydrophobic (P)
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

Involvement in disease:  Parkinson disease 2 (PARK2) [MIM:600116]: A neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually before 40. It differs from classic Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent. {ECO:0000269|PubMed:10072423, ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10939576, ECO:0000269|PubMed:11163284, ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11487568, ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, ECO:0000269|PubMed:12056932, ECO:0000269|PubMed:12112109, ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:12362318, ECO:0000269|PubMed:12397156, ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:17360614, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:9560156, ECO:0000269|PubMed:9731209}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Involvement in disease:  Parkinson disease (PARK) [MIM:168600]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. {ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:29311685}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease (PubMed:12730996 and PubMed:12629236).
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In PARK2 and PARK; induces a conformational change in the PSMD4-binding site of Ubl resulting in impaired proteasomal binding; decreases ubiquitination and degradation; increased aggregation; impairs the ability to ubiquitinate and degrade SYT11.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  42
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  465
The length of the canonical sequence.

Location on the sequence:   SIFQLKEVVAKRQGVPADQL  R VIFAGKELRNDWTVQNCDLD
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                         SIFQLKEVVAKRQGVPADQLRVIFAGKELRNDWTVQNCDLD

Mouse                         SILQLKEVVAKRQGVPADQLRVIFAGKELPNHLTVQNCDLE

Rat                           SIFQLKEVVAKRQGVPADQLRVIFAGKELQNHLTVQNCDLE

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.

TypePositionsDescription
Chain 1 – 465 E3 ubiquitin-protein ligase parkin
Domain 1 – 76 Ubiquitin-like
Alternative sequence 1 – 191 Missing. In isoform 4.
Alternative sequence 1 – 79 Missing. In isoform 3.
Beta strand 41 – 45


Literature citations

Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase.
Shimura H.; Hattori N.; Kubo S.; Mizuno Y.; Asakawa S.; Minoshima S.; Shimizu N.; Iwai K.; Chiba T.; Tanaka K.; Suzuki T.;
Nat. Genet. 25:302-305(2000)
Cited for: FUNCTION; CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND ARG-240;

Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease.
Shimura H.; Schlossmacher M.G.; Hattori N.; Frosch M.P.; Trockenbacher A.; Schneider R.; Mizuno Y.; Kosik K.S.; Selkoe D.J.;
Science 293:263-269(2001)
Cited for: FUNCTION; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND ARG-240;

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; UBIQUITINATION; CHARACTERIZATION OF VARIANT PARK2 PRO-42;

Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain mutant.
Rose J.M.; Novoselov S.S.; Robinson P.A.; Cheetham M.E.;
Hum. Mol. Genet. 20:16-27(2011)
Cited for: CHARACTERIZATION OF VARIANTS PARK2 PRO-42 AND GLY-289;

Evaluation of 50 probands with early-onset Parkinson's disease for parkin mutations.
Hedrich K.; Marder K.; Harris J.; Kann M.; Lynch T.; Meija-Santana H.; Pramstaller P.P.; Schwinger E.; Bressman S.B.; Fahn S.; Klein C.;
Neurology 58:1239-1246(2002)
Cited for: VARIANTS PARK2 PRO-42; LEU-192; CYS-256; TRP-275; ASP-430 AND LEU-437;

Novel parkin mutations detected in patients with early-onset Parkinson's disease.
Bertoli-Avella A.M.; Giroud-Benitez J.L.; Akyol A.; Barbosa E.; Schaap O.; van der Linde H.C.; Martignoni E.; Lopiano L.; Lamberti P.; Fincati E.; Antonini A.; Stocchi F.; Montagna P.; Squitieri F.; Marini P.; Abbruzzese G.; Fabbrini G.; Marconi R.; Dalla Libera A.; Trianni G.; Guidi M.; De Gaetano A.; Boff Maegawa G.; De Leo A.; Gallai V.; de Rosa G.; Vanacore N.; Meco G.; van Duijn C.M.; Oostra B.A.; Heutink P.; Bonifati V.;
Mov. Disord. 20:424-431(2005)
Cited for: VARIANTS PARK2 PRO-42; CYS-402; ASN-415 AND ARG-418;

Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson's disease-like pathology.
Wang C.; Kang X.; Zhou L.; Chai Z.; Wu Q.; Huang R.; Xu H.; Hu M.; Sun X.; Sun S.; Li J.; Jiao R.; Zuo P.; Zheng L.; Yue Z.; Zhou Z.;
Nat. Commun. 9:81-81(2018)
Cited for: CHARACTERIZATION OF VARIANTS PARK PRO-42 AND TRP-275; FUNCTION;

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.