UniProtKB/Swiss-Prot O60260: Variant p.Pro437Leu

E3 ubiquitin-protein ligase parkin
Gene: PARK2
Chromosomal location: 6q25.2-q27
Variant information

Variant position:  437
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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Proline (P) to Leucine (L) at position 437 (P437L, p.Pro437Leu).
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

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. 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.

Variant description:  In PARK2; impaired E3 ubiquitin-protein ligase toward BCL2.
Any additional useful information about the variant.

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



Sequence information

Variant position:  437
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:   PCPRCHVPVEKNGGCMHMKC  P QPQCRLEWCWNCGCEWNRVC
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                         PCPRCHVPVEKNGGCMHMKCPQPQCRLEWCWNCGCEWNRVC

Mouse                         PCPRCNVPIEKNGGCMHMKCPQPQCKLEWCWNCGCEWNRAC

Rat                           PCPRCNVPIEKNGGCMHMKCPQPQCKLEWCWNCGCEWNRAC

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
Zinc finger 418 – 449 RING-type 2
Active site 431 – 431
Alternative sequence 298 – 465 Missing. In isoform 3.
Alternative sequence 369 – 465 Missing. In isoform 5.
Mutagenesis 421 – 421 C -> A. Impairs the ability of self-ubiquitination and to ubiquitinate SNCAIP.
Mutagenesis 431 – 431 C -> S. Impairs the ability to ubiquitinate target proteins.
Mutagenesis 433 – 433 H -> NA. Impaired activity.
Mutagenesis 444 – 444 E -> QA. Impaired activity.


Literature citations

Parkin mono-ubiquitinates Bcl-2 and regulates autophagy.
Chen D.; Gao F.; Li B.; Wang H.; Xu Y.; Zhu C.; Wang G.;
J. Biol. Chem. 285:38214-38223(2010)
Cited for: FUNCTION; INTERACTION WITH BCL2; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS PARK2 ASN-161; ARG-240; PHE-431 AND LEU-437;

Linkage stratification and mutation analysis at the parkin locus identifies mutation positive Parkinson's disease families.
Nichols W.C.; Pankratz N.; Uniacke S.K.; Pauciulo M.W.; Halter C.; Rudolph A.; Conneally P.M.; Foroud T.;
J. Med. Genet. 39:489-492(2002)
Cited for: VARIANTS PARK2 ASN-211; TRP-275; ASP-430 AND LEU-437;

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;

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.
Oliveira S.A.; Scott W.K.; Martin E.R.; Nance M.A.; Watts R.L.; Hubble J.P.; Koller W.C.; Pahwa R.; Stern M.B.; Hiner B.C.; Ondo W.G.; Allen F.H. Jr.; Scott B.L.; Goetz C.G.; Small G.W.; Mastaglia F.; Stajich J.M.; Zhang F.; Booze M.W.; Winn M.P.; Middleton L.T.; Haines J.L.; Pericak-Vance M.A.; Vance J.M.;
Ann. Neurol. 53:624-629(2003)
Cited for: VARIANTS PARK2 GLN-33; GLU-82; ASP-430 AND LEU-437; VARIANTS PARK TYR-253; CYS-256; TRP-275 AND ASN-280; VARIANTS LEU-380 AND ASN-394;

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease.
Foroud T.; Uniacke S.K.; Liu L.; Pankratz N.; Rudolph A.; Halter C.; Shults C.; Marder K.; Conneally P.M.; Nichols W.C.;
Neurology 60:796-801(2003)
Cited for: VARIANTS PARK2 VAL-192; ASN-211; MET-240 AND LEU-437; VARIANT ASN-167; INVOLVEMENT IN LATE-ONSET PARK;

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.