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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q9NUW8: Variant p.His493Arg

Tyrosyl-DNA phosphodiesterase 1
Gene: TDP1
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Variant information Variant position: help 493 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help 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: help From Histidine (H) to Arginine (R) at position 493 (H493R, p.His493Arg). 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: help Change from medium size and polar (H) to large size and basic (R) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help 0 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: help In SCAN1; reduces enzyme activity and leads to the accumulation of covalent complexes between TDP1 and DNA. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 493 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 608 The length of the canonical sequence.
Location on the sequence: help LHSYFHKWSAETSGRSNAMP H IKTYMRPSPDFSKIAWFLVT 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences. 
Human                         LHSYFHKWSAETSGRSNAMP-HIKTYMRPSPD----------FSKIAWFLVT

Mouse                         LHSYFHKWSAETSGRSNAMP-HIKTYMRPSPD---------

Rat                           LHPYFHKWSAETSGRSNAMP-HIKTYMRPSPD---------

Caenorhabditis elegans        LQGNMCKWRSNAKRRTNAVP-HCKTYVKYDKK---------

Drosophila                    LKDYLQQWKSSDRFRSRAMP-HIKSYTRFNLE---------

Baker's yeast                 FKVFYKQDPAMVTRRRGTTPAHSKFYMHCATNSAGPCDASQ

Fission yeast                 KGKNLCKWVAMKAGRQRVAP-HIKTYMRFSND---------
Sequence annotation in neighborhood: help 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 – 608 Tyrosyl-DNA phosphodiesterase 1
Active site 493 – 493 Proton donor/acceptor
Binding site 495 – 495
Mutagenesis 493 – 493 H -> A. 3000-fold reduction in activity; abolishes hydrolysis of the covalent intermediate between the active site nucleophile and DNA.
Mutagenesis 493 – 493 H -> N. 15000-fold reduction in activity.
Mutagenesis 495 – 495 K -> A. Abolishes hydrolysis of the covalent intermediate between the active site nucleophile and DNA.
Mutagenesis 495 – 495 K -> S. 125-fold reduction in activity.



Literature citations
Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages.
Interthal H.; Chen H.J.; Champoux J.J.;
J. Biol. Chem. 280:36518-36528(2005)
Cited for: FUNCTION; CATALYTIC ACTIVITY; CHARACTERIZATION OF VARIANT SCAN1 ARG-493; Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.
Takashima H.; Boerkoel C.F.; John J.; Saifi G.M.; Salih M.A.M.; Armstrong D.; Mao Y.; Quiocho F.A.; Roa B.B.; Nakagawa M.; Stockton D.W.; Lupski J.R.;
Nat. Genet. 32:267-272(2002)
Cited for: VARIANT SCAN1 ARG-493; VARIANT LEU-566; TISSUE SPECIFICITY; Deficiency in 3'-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1).
Zhou T.; Lee J.W.; Tatavarthi H.; Lupski J.R.; Valerie K.; Povirk L.F.;
Nucleic Acids Res. 33:289-297(2005)
Cited for: CHARACTERIZATION OF VARIANT SCAN1 ARG-493; SUBCELLULAR LOCATION; PHOSPHORYLATION; SCAN1 mutant Tdp1 accumulates the enzyme-DNA intermediate and causes camptothecin hypersensitivity.
Interthal H.; Chen H.J.; Kehl-Fie T.E.; Zotzmann J.; Leppard J.B.; Champoux J.J.;
EMBO J. 24:2224-2233(2005)
Cited for: CHARACTERIZATION OF VARIANT SCAN1 ARG-493; Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?
Hirano R.; Interthal H.; Huang C.; Nakamura T.; Deguchi K.; Choi K.; Bhattacharjee M.B.; Arimura K.; Umehara F.; Izumo S.; Northrop J.L.; Salih M.A.M.; Inoue K.; Armstrong D.L.; Champoux J.J.; Takashima H.; Boerkoel C.F.;
EMBO J. 26:4732-4743(2007)
Cited for: CHARACTERIZATION OF VARIANT SCAN1 ARG-493; TISSUE SPECIFICITY;
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.