UniProtKB/SwissProt variant VAR

Variant information

Variant position:

62

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 Histidine (H) at position 62 (R62H, p.Arg62His).

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 (H)

The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:

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:

Does not affect protein structure; no effect on cell membrane localization; increases autophagy in microglia; decreases LDL, CLU and APOE binding; decreases LDL uptake into cells; no effect on CLU uptake into cells; decreases the uptake of APP-LDL complex in macrophages; decreases binding to oligomeric APP cleavage product beta-amyloid peptide 42.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs143332484 [ dbSNP | Ensembl ]

Sequence information

Variant position:

62

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

Protein sequence length:

230

The length of the canonical sequence.

Location on the sequence:

KHWGRRKAWCRQLGEKGPCQ R VVSTHNLWLLSFLRRWNGST

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                         KHWGRRKAWCRQLGEKGPCQRVVSTHNLWLLSFLRRWNGST

Mouse                         KHWGRRKAWCRQLGEEGPCQRVVSTHGVWLLAFLKKRNGST

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.

Type	Positions	Description
Chain	19 – 230	Triggering receptor expressed on myeloid cells 2
Topological domain	19 – 174	Extracellular
Domain	29 – 112	Ig-like V-type
Binding site	67 – 67	Phosphatidylserine
Binding site	68 – 68	Phosphatidylserine; via amide nitrogen
Binding site	77 – 77	Phosphatidylserine
Glycosylation	79 – 79	N-linked (GlcNAc...) asparagine
Disulfide bond	36 – 110
Mutagenesis	48 – 48	K -> M. Loss of LDL, CLU and APOE binding.
Mutagenesis	60 – 60	C -> A. Loss of proteolytic cleavage by ADAM10 and ectodomain shedding. Decreases protein maturation and cell membrane localization.
Mutagenesis	68 – 68	N -> K. No effect on cell membrane localization.
Mutagenesis	76 – 76	R -> D. Decreases binding to THP-1 cells.
Mutagenesis	77 – 77	R -> D. Decreases binding to THP-1 cells.
Beta strand	60 – 66

Literature citations

TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.
Yeh F.L.; Wang Y.; Tom I.; Gonzalez L.C.; Sheng M.;
Neuron 91:328-340(2016)
Cited for: FUNCTION; TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANTS CYS-38; HIS-47; HIS-62; MET-66 AND ASN-87; MUTAGENESIS OF LYS-48;

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.
Ulland T.K.; Song W.M.; Huang S.C.; Ulrich J.D.; Sergushichev A.; Beatty W.L.; Loboda A.A.; Zhou Y.; Cairns N.J.; Kambal A.; Loginicheva E.; Gilfillan S.; Cella M.; Virgin H.W.; Unanue E.R.; Wang Y.; Artyomov M.N.; Holtzman D.M.; Colonna M.;
Cell 170:649-663(2017)
Cited for: TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62;

TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function.
Zhao Y.; Wu X.; Li X.; Jiang L.L.; Gui X.; Liu Y.; Sun Y.; Zhu B.; Pina-Crespo J.C.; Zhang M.; Zhang N.; Chen X.; Bu G.; An Z.; Huang T.Y.; Xu H.;
Neuron 97:1023-1031(2018)
Cited for: FUNCTION; CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62;

Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms.
Kober D.L.; Alexander-Brett J.M.; Karch C.M.; Cruchaga C.; Colonna M.; Holtzman M.J.; Brett T.J.;
Elife 5:E20391-E20391(2016)
Cited for: X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 19-133; DISULFIDE BONDS; SUBUNIT; SUBCELLULAR LOCATION; MUTAGENESIS OF ASN-68; ARG-76 AND ARG-77; GLYCOSYLATION AT ASN-79; CHARACTERIZATION OF VARIANTS CYS-38; HIS-47; HIS-62; MET-66; ASN-87 AND LYS-96; CHARACTERIZATION OF VARIANT PLOSL2 GLY-126;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q9NZC2: Variant p.Arg62His