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UniProtKB/Swiss-Prot O60260: Variant p.Gly430Asp

E3 ubiquitin-protein ligase parkin
Gene: PRKN
Variant information

Variant position:  430
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 Glycine (G) to Aspartate (D) at position 430 (G430D, p.Gly430Asp).
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 glycine (G) to medium size and acidic (D)
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 PARK2; impairs PINK1-dependent localization to dysfunctional depolarized mitochondria; impaired E3 ubiquitin-protein ligase toward ZNF746.
Any additional useful information about the variant.

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

Sequence information

Variant position:  430
The position of the amino-acid change on the UniProtKB canonical protein sequence.

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

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.




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.

Chain 1 – 465 E3 ubiquitin-protein ligase parkin
Zinc finger 418 – 449 RING-type 2; atypical
Region 234 – 465 TRIAD supradomain
Active site 431 – 431
Metal binding 418 – 418 Zinc 5
Metal binding 421 – 421 Zinc 5
Metal binding 436 – 436 Zinc 5
Metal binding 441 – 441 Zinc 5
Metal binding 446 – 446 Zinc 6
Metal binding 449 – 449 Zinc 6
Alternative sequence 298 – 465 Missing. In isoform 3.
Alternative sequence 369 – 465 Missing. In isoform 5.
Mutagenesis 415 – 415 T -> N. Loss of activity and self-ubiquitination. Loss of monoubiquitination resulting in an increase in apoptosis. No effect on polyubiquitination or mitophagy.
Mutagenesis 421 – 421 C -> A. Impairs the ability of self-ubiquitination and to ubiquitinate SNCAIP.
Mutagenesis 429 – 429 G -> E. Reduced self-ubiquitination.
Mutagenesis 430 – 430 G -> D. Loss of self-ubiquitination.
Mutagenesis 431 – 431 C -> A. Loss of activity.
Mutagenesis 431 – 431 C -> S. Impairs the ability to ubiquitinate target proteins. No effect on translocation to mitochondria.
Mutagenesis 433 – 433 H -> NA. Impaired activity.
Mutagenesis 444 – 444 E -> QA. Impaired activity.
Beta strand 429 – 431

Literature citations

PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.
Vives-Bauza C.; Zhou C.; Huang Y.; Cui M.; de Vries R.L.; Kim J.; May J.; Tocilescu M.A.; Liu W.; Ko H.S.; Magrane J.; Moore D.J.; Dawson V.L.; Grailhe R.; Dawson T.M.; Li C.; Tieu K.; Przedborski S.;
Proc. Natl. Acad. Sci. U.S.A. 107:378-383(2010)

PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease.
Shin J.H.; Ko H.S.; Kang H.; Lee Y.; Lee Y.I.; Pletinkova O.; Troconso J.C.; Dawson V.L.; Dawson T.M.;
Cell 144:689-702(2011)

Association between early-onset Parkinson's disease and mutations in the parkin gene.
Luecking C.B.; Duerr A.; Bonifati V.; Vaughan J.R.; De Michele G.; Gasser T.; Harhangi B.S.; Meco G.; Denefle P.; Wood N.W.; Agid Y.; Brice A.;
N. Engl. J. Med. 342:1560-1567(2000)
Cited for: VARIANTS PARK2 ASN-161; ASN-211; CYS-256; TRP-275; ASN-280; GLY-289; GLU-328; ASN-415 AND ASP-430; VARIANT CYS-334;

Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from founder effects.
Periquet M.; Luecking C.B.; Vaughan J.R.; Bonifati V.; Duerr A.; De Michele G.; Horstink M.; Farrer M.; Illarioshkin S.N.; Pollak P.; Borg M.; Brefel-Courbon C.; Denefle P.; Meco G.; Gasser T.; Breteler M.M.; Wood N.W.; Agid Y.; Brice A.;
Am. J. Hum. Genet. 68:617-626(2001)
Cited for: VARIANTS PARK2 ASN-211; TRP-275 AND ASP-430;

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;

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.