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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P31749: Variant p.Glu17Lys

RAC-alpha serine/threonine-protein kinase
Gene: AKT1
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Variant information Variant position: help 17 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 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: help 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: help 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: help 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: help Links to websites of interest for the variant.


Sequence information Variant position: help 17 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 480 The length of the canonical sequence.
Location on the sequence: help 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences. 
Human                         MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIG

Mouse                         MNDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIG

Rat                           MNDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIG

Bovine                        MNDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIG

Xenopus laevis                MNEVAIVKEGWLHKRGEYIKTWRPRYFLLKSDGTFIG

Caenorhabditis elegans        RRQEDVVIEGWLHKKGEHIRNWRPRYFMIFNDGALLG

Drosophila                    TEQTQVVKEGWLMKRGEHIKNWRQRYFVLHSDGRLMG
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 – 480 RAC-alpha serine/threonine-protein kinase
Domain 5 – 108 PH
Binding site 14 – 19
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
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.
Inoki K.; Li Y.; Zhu T.; Wu J.; Guan K.L.;
Nat. Cell Biol. 4:648-657(2002)
Cited for: FUNCTION; CATALYTIC ACTIVITY; MUTAGENESIS OF LYS-179; 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; RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation.
Li T.; Wang X.; Ju E.; da Silva S.R.; Chen L.; Zhang X.; Wei S.; Gao S.J.;
Nat. Commun. 12:1055-1055(2021)
Cited for: FUNCTION; CATALYTIC ACTIVITY; MUTAGENESIS OF LYS-179; 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;
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.