View source for 2uzs


==A transforming mutation in the pleckstrin homology domain of AKT1 in cancer (AKT1-PH_E17K)==
<StructureSection load='2uzs' size='340' side='right'caption='[[2uzs]], [[Resolution|resolution]] 2.46&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2uzs]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2UZS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2UZS FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.46&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4IP:INOSITOL-(1,3,4,5)-TETRAKISPHOSPHATE'>4IP</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2uzs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uzs OCA], [https://pdbe.org/2uzs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2uzs RCSB], [https://www.ebi.ac.uk/pdbsum/2uzs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2uzs ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN] Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 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.  Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].  Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.  Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:[https://omim.org/entry/176920 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.<ref>PMID:18954143</ref> <ref>PMID:21793738</ref> 
== Function ==
[https://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref>   AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/uz/2uzs_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2uzs ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.,Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE Nature. 2007 Jul 26;448(7152):439-44. Epub 2007 Jul 4. PMID:17611497<ref>PMID:17611497</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2uzs" style="background-color:#fffaf0;"></div>

==See Also==
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bittner M]]
[[Category: Blanchard KL]]
[[Category: Boguslawski S]]
[[Category: Briggs SL]]
[[Category: Carpten JD]]
[[Category: Donoho GP]]
[[Category: Du J]]
[[Category: Faber AL]]
[[Category: Horn C]]
[[Category: Hostetter G]]
[[Category: Lai MH]]
[[Category: Lin A]]
[[Category: Moses TY]]
[[Category: Mousses S]]
[[Category: Patel K]]
[[Category: Qian YW]]
[[Category: Robbins CM]]
[[Category: Savage S]]
[[Category: Schevitz R]]
[[Category: Thomas JE]]
[[Category: Touchman J]]
[[Category: Tucker-Kellogg G]]
[[Category: Uhlik M]]
[[Category: Zeckner DJ]]