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2kyl

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2kyl, 10 NMR models ()
Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Solution structure of MAST2-PDZ complexed with the C-terminus of PTEN

Publication Abstract from PubMed

PTEN (phosphatase and tensin homolog deleted on chromosome 10) and MAST2 (microtubule-associated serine and threonine kinase 2) interact with each other through the PDZ domain of MAST2 (MAST2-PDZ) and the carboxyl-terminal (C-terminal) PDZ domain-binding site (PDZ-BS) of PTEN. These two proteins function as negative regulators of cell survival pathways, and silencing of either one promotes neuronal survival. In human neuroblastoma cells infected with rabies virus (RABV), the C-terminal PDZ domain of the viral glycoprotein (G protein) can target MAST2-PDZ, and RABV infection triggers neuronal survival in a PDZ-BS-dependent fashion. These findings suggest that the PTEN-MAST2 complex inhibits neuronal survival and that viral G protein disrupts this complex through competition with PTEN for binding to MAST2-PDZ. We showed that the C-terminal sequences of PTEN and the viral G protein bound to MAST2-PDZ with similar affinities. Nuclear magnetic resonance structures of these complexes exhibited similar large interaction surfaces, providing a structural basis for their binding specificities. Additionally, the viral G protein promoted the nuclear exclusion of PTEN in infected neuroblastoma cells in a PDZ-BS-dependent manner without altering total PTEN abundance. These findings suggest that formation of the PTEN-MAST2 complex is specifically affected by the viral G protein and emphasize how disruption of a critical protein-protein interaction regulates intracellular PTEN trafficking. In turn, the data show how the viral protein might be used to decipher the underlying molecular mechanisms and to clarify how the subcellular localization of PTEN regulates neuronal survival.

Interference with the PTEN-MAST2 interaction by a viral protein leads to cellular relocalization of PTEN., Terrien E, Chaffotte A, Lafage M, Khan Z, Prehaud C, Cordier F, Simenel C, Delepierre M, Buc H, Lafon M, Wolff N, Sci Signal. 2012 Aug 14;5(237):ra58. doi: 10.1126/scisignal.2002941. PMID:022894835

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[PTEN_HUMAN] Defects in PTEN are a cause of Cowden disease (CD) [MIM:158350]; also known as Cowden syndrome (CS). CD is an autosomal dominant cancer predisposition syndrome associated with elevated risk for tumors of the breast, thyroid and skin. The predominant phenotype for CD is multiple hamartoma syndrome, in many organ systems including the breast (70% of CD patients), thyroid (40-60%), skin, CNS (40%), gastrointestinal tract. Affected individuals are at an increased risk of both breast and thyroid cancers. Trichilemmomas (benign tumors of the hair follicle infundibulum), and mucocutaneous papillomatosis (99%) are hallmarks of CD.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Defects in PTEN are the cause of Lhermitte-Duclos disease (LDD) [MIM:158350]; also known as cerebelloparenchymal disorder VI. LDD is characterized by dysplastic gangliocytoma of the cerebellum which often results in cerebellar signs and seizures. LDD and CD seem to be the same entity, and are considered as hamartoma-neoplasia syndromes. Defects in PTEN are a cause of Bannayan-Zonana syndrome (BZS) [MIM:153480]; also known as Ruvalcaba-Myhre-Smith syndrome (RMSS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS). In BZS there seems not to be an increased risk of malignancy. It has a partial clinical overlap with CD. BZS is characterized by the classic triad of macrocephaly, lipomatosis and pigmented macules of the gland penis.[19][20][21][22][23] Defects in PTEN are a cause of head and neck squamous cell carcinomas (HNSCC) [MIM:275355]; also known as squamous cell carcinoma of the head and neck.[24] Defects in PTEN are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089]. Note=PTEN mutations are found in a subset of patients with Proteus syndrome, a genetically heterogeneous condition. The molecular diagnosis of PTEN mutation positive cases classifies Proteus syndrome patients as part of the PTEN hamartoma syndrome spectrum. As such, patients surviving the early years of Proteus syndrome are likely at a greater risk of developing malignancies. Defects in PTEN are a cause of susceptibility to glioma type 2 (GLM2) [MIM:613028]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Defects in PTEN are a cause of VACTERL association with hydrocephalus (VACTERL-H) [MIM:276950]. VACTERL is an acronym for vertebral anomalies, anal atresia, congenital cardiac disease, tracheoesophageal fistula, renal anomalies, radial dysplasia, and other limb defects. Defects in PTEN may be a cause of susceptibility to prostate cancer (PC) [MIM:176807]. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Defects in PTEN are a cause of macrocephaly/autism syndrome (MCEPHAS) [MIM:605309]. Patients have autism spectrum disorders and macrocephaly, with head circumferences ranging from +2.5 to +8 SD for age and sex (average head circumference +4.0 SD).[25] Note=A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.

Function

[MAST2_HUMAN] Appears to link the dystrophin/utrophin network with microtubule filaments via the syntrophins. Phosphorylation of DMD or UTRN may modulate their affinities for associated proteins. Functions in a multi-protein complex in spermatid maturation. Regulates lipopolysaccharide-induced IL-12 synthesis in macrophages by forming a complex with TRAF6, resulting in the inhibition of TRAF6 NF-kappa-B activation (By similarity).[UniProtKB:Q60592] [PTEN_HUMAN] Tumor suppressor. Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins. Also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 > PtdIns(3,4)P2 > PtdIns3P > Ins(1,3,4,5)P4. The lipid phosphatase activity is critical for its tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form cooperates with AIP1 to suppress AKT1 activation. Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation. Plays a role as a 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. May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability.[26][27][28][29][30][31][32][33]

About this Structure

2kyl is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA.

Reference

  1. Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R, Tonks NK. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9052-7. PMID:9256433
  2. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13513-8. PMID:9811831
  3. Tsou HC, Teng DH, Ping XL, Brancolini V, Davis T, Hu R, Xie XX, Gruener AC, Schrager CA, Christiano AM, Eng C, Steck P, Ott J, Tavtigian SV, Peacocke M. The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet. 1997 Nov;61(5):1036-43. PMID:9345101 doi:S0002-9297(07)60192-X
  4. Lynch ED, Ostermeyer EA, Lee MK, Arena JF, Ji H, Dann J, Swisshelm K, Suchard D, MacLeod PM, Kvinnsland S, Gjertsen BT, Heimdal K, Lubs H, Moller P, King MC. Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet. 1997 Dec;61(6):1254-60. PMID:9399897 doi:10.1086/301639
  5. Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW, Kremer H. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997 Aug;6(8):1383-7. PMID:9259288
  6. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May;16(1):64-7. PMID:9140396 doi:10.1038/ng0597-64
  7. Chi SG, Kim HJ, Park BJ, Min HJ, Park JH, Kim YW, Dong SH, Kim BH, Lee JI, Chang YW, Chang R, Kim WK, Yang MH. Mutational abrogation of the PTEN/MMAC1 gene in gastrointestinal polyps in patients with Cowden disease. Gastroenterology. 1998 Nov;115(5):1084-9. PMID:9797362
  8. Tsou HC, Ping XL, Xie XX, Gruener AC, Zhang H, Nini R, Swisshelm K, Sybert V, Diamond TM, Sutphen R, Peacocke M. The genetic basis of Cowden's syndrome: three novel mutations in PTEN/MMAC1/TEP1. Hum Genet. 1998 Apr;102(4):467-73. PMID:9600246
  9. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, Liaw D, Caron S, Duboue B, Lin AY, Richardson AL, Bonnetblanc JM, Bressieux JM, Cabarrot-Moreau A, Chompret A, Demange L, Eeles RA, Yahanda AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV, Huson S, Lacombe D, Eng C, et al.. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998 Mar;7(3):507-15. PMID:9467011
  10. Scala S, Bruni P, Lo Muzio L, Mignogna M, Viglietto G, Fusco A. Novel mutation of the PTEN gene in an Italian Cowden's disease kindred. Int J Oncol. 1998 Oct;13(4):665-8. PMID:9735393
  11. Marsh DJ, Dahia PL, Caron S, Kum JB, Frayling IM, Tomlinson IP, Hughes KS, Eeles RA, Hodgson SV, Murday VA, Houlston R, Eng C. Germline PTEN mutations in Cowden syndrome-like families. J Med Genet. 1998 Nov;35(11):881-5. PMID:9832031
  12. Olschwang S, Serova-Sinilnikova OM, Lenoir GM, Thomas G. PTEN germ-line mutations in juvenile polyposis coli. Nat Genet. 1998 Jan;18(1):12-4. PMID:9425889 doi:10.1038/ng0198-12
  13. Kurose K, Araki T, Matsunaka T, Takada Y, Emi M. Variant manifestation of Cowden disease in Japan: hamartomatous polyposis of the digestive tract with mutation of the PTEN gene. Am J Hum Genet. 1999 Jan;64(1):308-10. PMID:9915974 doi:10.1086/302207
  14. Sutphen R, Diamond TM, Minton SE, Peacocke M, Tsou HC, Root AW. Severe Lhermitte-Duclos disease with unique germline mutation of PTEN. Am J Med Genet. 1999 Feb 12;82(4):290-3. PMID:10051160
  15. Nelen MR, Kremer H, Konings IB, Schoute F, van Essen AJ, Koch R, Woods CG, Fryns JP, Hamel B, Hoefsloot LH, Peeters EA, Padberg GW. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet. 1999 Apr;7(3):267-73. PMID:10234502 doi:10.1038/sj.ejhg.5200289
  16. Han SY, Kato H, Kato S, Suzuki T, Shibata H, Ishii S, Shiiba K, Matsuno S, Kanamaru R, Ishioka C. Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. Cancer Res. 2000 Jun 15;60(12):3147-51. PMID:10866302
  17. Weng LP, Brown JL, Eng C. PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum Mol Genet. 2001 Mar 15;10(6):599-604. PMID:11230179
  18. Marsh DJ, Theodosopoulos G, Howell V, Richardson AL, Benn DE, Proos AL, Eng C, Robinson BG. Rapid mutation scanning of genes associated with familial cancer syndromes using denaturing high-performance liquid chromatography. Neoplasia. 2001 May-Jun;3(3):236-44. PMID:11494117 doi:10.1038/sj/neo/7900154
  19. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, Liaw D, Caron S, Duboue B, Lin AY, Richardson AL, Bonnetblanc JM, Bressieux JM, Cabarrot-Moreau A, Chompret A, Demange L, Eeles RA, Yahanda AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV, Huson S, Lacombe D, Eng C, et al.. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998 Mar;7(3):507-15. PMID:9467011
  20. Han SY, Kato H, Kato S, Suzuki T, Shibata H, Ishii S, Shiiba K, Matsuno S, Kanamaru R, Ishioka C. Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. Cancer Res. 2000 Jun 15;60(12):3147-51. PMID:10866302
  21. Marsh DJ, Theodosopoulos G, Howell V, Richardson AL, Benn DE, Proos AL, Eng C, Robinson BG. Rapid mutation scanning of genes associated with familial cancer syndromes using denaturing high-performance liquid chromatography. Neoplasia. 2001 May-Jun;3(3):236-44. PMID:11494117 doi:10.1038/sj/neo/7900154
  22. Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, Eng C. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet. 1997 Aug;16(4):333-4. PMID:9241266 doi:10.1038/ng0897-333
  23. Marsh DJ, Kum JB, Lunetta KL, Bennett MJ, Gorlin RJ, Ahmed SF, Bodurtha J, Crowe C, Curtis MA, Dasouki M, Dunn T, Feit H, Geraghty MT, Graham JM Jr, Hodgson SV, Hunter A, Korf BR, Manchester D, Miesfeldt S, Murday VA, Nathanson KL, Parisi M, Pober B, Romano C, Eng C, et al.. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet. 1999 Aug;8(8):1461-72. PMID:10400993
  24. Poetsch M, Lorenz G, Kleist B. Detection of new PTEN/MMAC1 mutations in head and neck squamous cell carcinomas with loss of chromosome 10. Cancer Genet Cytogenet. 2002 Jan 1;132(1):20-4. PMID:11801303
  25. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet. 2005 Apr;42(4):318-21. PMID:15805158 doi:10.1136/jmg.2004.024646
  26. Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997 Jun 1;57(11):2124-9. PMID:9187108
  27. Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R, Tonks NK. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9052-7. PMID:9256433
  28. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998 May 29;273(22):13375-8. PMID:9593664
  29. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13513-8. PMID:9811831
  30. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998 Jun 5;280(5369):1614-7. PMID:9616126
  31. Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H. The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10182-7. PMID:10468583
  32. Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem. 2001 Dec 28;276(52):48627-30. Epub 2001 Nov 13. PMID:11707428 doi:10.1074/jbc.C100556200
  33. Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature. 2008 Oct 9;455(7214):813-7. doi: 10.1038/nature07290. Epub 2008 Aug 20. PMID:18716620 doi:10.1038/nature07290

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