UniProtKB/SwissProt variant VAR

Variant information

Variant position:

17

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 implicated in disease according to literature reports.
Polymorphism: Variants not reported to be implicated in disease.
Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:

From Glutamate (E) to Lysine (K) at position 17 (E17K, p.Glu17Lys).

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 medium size and acidic (E) to large size and basic (K)

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

Involvement in disease:

Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:17611497}. Note=Disease susceptibility is associated with variations 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.

Involvement in disease:

Proteus syndrome (PROTEUSS) [MIM:176920]: A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes. {ECO:0000269|PubMed:18954143, ECO:0000269|PubMed:21793738}. 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 PROTEUSS and breast cancer; also detected in colorectal and ovarian cancer; somatic mutation; results in increased phosphorylation at T-308 and higher basal ubiquitination; the mutant protein is more efficiently recruited to the plasma membrane; alters phosphatidylinositiol phosphates lipid specificity of the AKT1 PH domain.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs121434592 [ dbSNP | Ensembl ]

Sequence information

Variant position:

17

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

Protein sequence length:

480

The length of the canonical sequence.

Location on the sequence:

MSDVAIVKEGWLHKRG E YIKTWRPRYFLLKNDGTFIG

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                         MS-----------------------------------------------------------------------------------------------------DVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIG

Mouse                         MN-----------------------------------

Rat                           MN-----------------------------------

Bovine                        MN-----------------------------------

Xenopus laevis                MN-----------------------------------

Caenorhabditis elegans        MSMTSLSTKSRR-------------------------

Drosophila                    MNYLPFVLQRRSTVVASAPAPGSASRIPESPTTTGSN

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	1 – 480	RAC-alpha serine/threonine-protein kinase
Domain	5 – 108	PH
Region	14 – 19	Inositol-(1,3,4,5)-tetrakisphosphate binding
Modified residue	14 – 14	N6-acetyllysine
Modified residue	20 – 20	N6-acetyllysine
Alternative sequence	1 – 62	Missing. In isoform 2.
Mutagenesis	8 – 8	K -> R. Substantial reduction of ubiquitination, phosphorylation at T-308 and S-473, AKT activation as well as IGF1-induced membrane recruitment. Decrease in ubiquitination and phosphorylation at T-308 as well as impaired association with the membrane; when associated with K-17.
Mutagenesis	14 – 14	K -> A. Impairs interaction with PtdIns(3,4,5)P3 and PtdIns(3,4)P2.
Mutagenesis	14 – 14	K -> Q. Substantial reduction of phosphorylation at T-308 and S-473, loss of AKT activation, and loss of binding to PIP3 as well as IGF1-induced membrane recruitment.
Mutagenesis	14 – 14	K -> R. Substantial reduction of ubiquitination, phosphorylation at T-308 and S-473, AKT activation, loss of binding to PIP3 as well as IGF1-induced membrane recruitment.
Mutagenesis	17 – 17	E -> K. No effect on membrane localization. Loss of membrane localization; when associated with Q-20.
Mutagenesis	20 – 20	K -> Q. Substantial reduction of phosphorylation at T-308 and S-473, reduced AKT activation, and reduced binding to PIP3 as well as IGF1-induced membrane recruitment. Loss of membrane localization; when associated with K-17.
Mutagenesis	20 – 20	K -> R. Slight increase of phosphorylation at T-308 and S-473.
Mutagenesis	25 – 25	R -> AC. Impairs interaction with PtdIns(3,4,5)P3 and PtdIns(3,4)P2.
Beta strand	17 – 19

Literature citations

The E3 ligase TRAF6 regulates Akt ubiquitination and activation.
Yang W.-L.; Wang J.; Chan C.-H.; Lee S.-W.; Campos A.D.; Lamothe B.; Hur L.; Grabiner B.C.; Lin X.; Darnay B.G.; Lin H.-K.;
Science 325:1134-1138(2009)
Cited for: UBIQUITINATION; INTERACTION WITH TRAF6; MUTAGENESIS OF LYS-8 AND LYS-14; CHARACTERIZATION OF VARIANT BREAST CANCER LYS-17;

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
Carpten J.D.; Faber A.L.; Horn C.; Donoho G.P.; Briggs S.L.; Robbins C.M.; Hostetter G.; Boguslawski S.; Moses T.Y.; Savage S.; Uhlik M.; Lin A.; Du J.; Qian Y.-W.; Zeckner D.J.; Tucker-Kellogg G.; Touchman J.; Patel K.; Mousses S.; Bittner M.; Schevitz R.; Lai M.-H.T.; Blanchard K.L.; Thomas J.E.;
Nature 448:439-444(2007)
Cited for: VARIANT BREAST CANCER LYS-17; CHARACTERIZATION OF VARIANT BREAST CANCER LYS-17;

Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain.
Landgraf K.E.; Pilling C.; Falke J.J.;
Biochemistry 47:12260-12269(2008)
Cited for: CHARACTERIZATION OF VARIANT PROTEUSS LYS-17;

A mosaic activating mutation in AKT1 associated with the Proteus syndrome.
Lindhurst M.J.; Sapp J.C.; Teer J.K.; Johnston J.J.; Finn E.M.; Peters K.; Turner J.; Cannons J.L.; Bick D.; Blakemore L.; Blumhorst C.; Brockmann K.; Calder P.; Cherman N.; Deardorff M.A.; Everman D.B.; Golas G.; Greenstein R.M.; Kato B.M.; Keppler-Noreuil K.M.; Kuznetsov S.A.; Miyamoto R.T.; Newman K.; Ng D.; O'Brien K.; Rothenberg S.; Schwartzentruber D.J.; Singhal V.; Tirabosco R.; Upton J.; Wientroub S.; Zackai E.H.; Hoag K.; Whitewood-Neal T.; Robey P.G.; Schwartzberg P.L.; Darling T.N.; Tosi L.L.; Mullikin J.C.; Biesecker L.G.;
N. Engl. J. Med. 365:611-619(2011)
Cited for: VARIANT PROTEUSS LYS-17;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P31749: Variant p.Glu17Lys