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UniProtKB/Swiss-Prot O60603: Variant p.Arg753Gln

Toll-like receptor 2
Gene: TLR2
Variant information

Variant position:  753
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LB/B
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 Arginine (R) to Glutamine (Q) at position 753 (R753Q, p.Arg753Gln).
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 polar (Q)
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

Polymorphism:  Genetic variations in TLR2 are associated with susceptibility to leprosy [MIM:246300]. Leprosy is a chronic disease associated with depressed cellular (but not humoral) immunity, the bacterium requires a lower temperature than 37 degrees Celsius and thrives particularly in peripheral Schwann cells and macrophages. The Trp-677 polymorphism in the intracellular domain of TLR2 has a role in susceptibility to lepromatous leprosy. Wild-type TLR2 mediates CD14-enhanced Mycobacterium leprae-dependent activation of NFKB1, but TLR2 containing the Trp-677 polymorphism did not. The impaired function of the Trp-677 polymorphism provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy.
Additional information on the polymorphism described.

Variant description:  Reduces TLR2-mediated NF-kappa-B activation.
Any additional useful information about the variant.

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

Sequence information

Variant position:  753
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  784
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.

Human                         ILILLEPIEKKAIPQ---RFCKLRKIMNTKTY-------------LEWPMDEAQREG

Gorilla                       ILILLEPIEKKAIPQ---RFCKLRKIMNTKTY---------


Rhesus macaque                ILVLLEPIEKKAIPQ---RFCKLRKIMNTKTY---------

Chimpanzee                    ILILLEPIEKKAIPQ---RFCKLRKIMNTKTY---------

Mouse                         ILVLLEPIERKAIPQ---RFCKLRKIMNTKTY---------

Bovine                        ILILLEPIDKKAIPQ---RFCKLRKIMNTKTY---------

Goat                          ILILLEPIDKKAIPQ---RFCKLRKIMNTKTY---------

Sheep                         ILILLEPIDKKAVPQ---RFCKLRKIMNTRTY---------

Horse                         ILILLEPIDKKAIPQ---RFCKLRKIMNTKTY---------


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 21 – 784 Toll-like receptor 2
Topological domain 610 – 784 Cytoplasmic
Domain 639 – 782 TIR
Cross 754 – 754 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Mutagenesis 751 – 751 K -> R. Reduced protein stability.
Mutagenesis 754 – 754 K -> R. Loss of PPP1R11-mediated ubiquitination and degradation.
Helix 750 – 758

Literature citations

The heterogeneous allelic repertoire of human Toll-Like receptor (TLR) genes.
Georgel P.; Macquin C.; Bahram S.;
PLoS ONE 4:E7803-E7803(2009)

Functional characterization of naturally occurring genetic variants in the human TLR1-2-6 gene family.
Ben-Ali M.; Corre B.; Manry J.; Barreiro L.B.; Quach H.; Boniotto M.; Pellegrini S.; Quintana-Murci L.;
Hum. Mutat. 32:643-652(2011)

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.