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PDBsum entry 2a5e

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protein links
Anti-oncogene PDB id
2a5e
Jmol
Contents
Protein chain
156 a.a. *
* Residue conservation analysis
PDB id:
2a5e
Name: Anti-oncogene
Title: Solution nmr structure of tumor suppressor p16ink4a, restrained minimized mean structure
Structure: Tumor suppressor p16ink4a. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
NMR struc: 1 models
Authors: I.-J.L.Byeon,J.Li,K.Ericson,T.L.Selby,A.Tevelev,H.-J.Kim, P.O'Maille,M.-D.Tsai
Key ref:
I.J.Byeon et al. (1998). Tumor suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4. Mol Cell, 1, 421-431. PubMed id: 9660926 DOI: 10.1016/S1097-2765(00)80042-8
Date:
13-Feb-98     Release date:   13-Aug-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P42771  (CD2A1_HUMAN) -  Cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3
Seq:
Struc:
156 a.a.
156 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     senescence-associated heterochromatin focus   4 terms 
  Biological process     senescence-associated heterochromatin focus assembly   18 terms 
  Biochemical function     protein binding     5 terms  

 

 
DOI no: 10.1016/S1097-2765(00)80042-8 Mol Cell 1:421-431 (1998)
PubMed id: 9660926  
 
 
Tumor suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4.
I.J.Byeon, J.Li, K.Ericson, T.L.Selby, A.Tevelev, H.J.Kim, P.O'Maille, M.D.Tsai.
 
  ABSTRACT  
 
The solution structure of the tumor suppressor p16INK4A has been determined by NMR, and important recognition regions of both cdk4 and p16INK4A have been identified. The tertiary structure of p16INK4A contains four helix-turn-helix motifs linked by three loops. Twelve tumorigenic mutants of p16INK4A have been constructed and analyzed for their structure and activity, and new mutants have been designed rationally. A fragment of 58 residues at the N terminus of cdk4 important for p16INK4A binding has been identified. The importance of this region was further verified by mutational analysis of cdk4. These results and docking experiments have been used to assess possible modes of binding between p16INK4A and cdk4.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. Assay of p16 ActivityGels of in vitro phosphorylation of pRb by cdk4 in the presence of increasing concentrations of wild-type p16 (A) and D84H (B). Lanes 1 and 2 are negative controls.
Figure 7.
Figure 7. Working Model for the C5–p16 ComplexThe model is depicted such that the ionic interactions between specific charged residues are visible. Side chains of Arg-24 and Glu-7 of C5 (blue ribbon) are shown in ball-and-stick mode. The p16 residue facing C5/Arg-24 is Glu-69, and that facing C5/Glu-7 is Arg-47. C5/Lys-22 could interact with p16/Asp-74. The p16 structure shown is 140° rotated from that in Figure 3B.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (1998, 1, 421-431) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20212158 E.Kovacs, P.Tompa, K.Liliom, and L.Kalmar (2010).
Dual coding in alternative reading frames correlates with intrinsic protein disorder.
  Proc Natl Acad Sci U S A, 107, 5429-5434.  
19690981 K.Kiwerska, M.Rydzanicz, A.Kram, M.Pastok, A.Antkowiak, W.Domagała, and K.Szyfter (2010).
Mutational analysis of CDKN2A gene in a group of 390 larynx cancer patients.
  Mol Biol Rep, 37, 325-332.  
21053367 N.Fahham, S.Sardari, S.N.Ostad, B.Vaziri, and M.H.Ghahremani (2010).
C-terminal domain of p16(INK4a) is adequate in inducing cell cycle arrest, growth inhibition and CDK4/6 interaction similar to the full length protein in HT-1080 fibrosarcoma cells.
  J Cell Biochem, 111, 1598-1606.  
20152798 Y.Guo, C.Yuan, C.M.Weghorst, and J.Li (2010).
IKKbeta specifically binds to P16 and phosphorylates Ser8 of P16.
  Biochem Biophys Res Commun, 393, 504-508.  
19260062 C.Kannengiesser, S.Brookes, A.G.del Arroyo, D.Pham, J.Bombled, M.Barrois, O.Mauffret, M.F.Avril, A.Chompret, G.M.Lenoir, A.Sarasin, G.Peters, B.Bressac-de Paillerets, F.Boitier, V.Bonadonna, J.M.Bonnetblanc, J.Chiesa, I.Coupier, S.Dalle, F.Grange, B.Guillot, P.Joly, C.Lasset, D.Leroux, J.M.Limacher, M.Longy, T.Martin-Denavit, L.Thomas, and P.Vabres (2009).
Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients.
  Hum Mutat, 30, 564-574.  
19643034 J.Aguirre-Hernández, B.S.Milne, C.Queen, P.C.O'Brien, T.Hoather, S.Haugland, M.A.Ferguson-Smith, J.M.Dobson, and D.R.Sargan (2009).
Disruption of chromosome 11 in canine fibrosarcomas highlights an unusual variability of CDKN2B in dogs.
  BMC Vet Res, 5, 27.  
18951449 F.J.Couch, L.J.Rasmussen, R.Hofstra, A.N.Monteiro, M.S.Greenblatt, N.de Wind, P.Boffetta, F.Couch, N.de Wind, D.Easton, D.Eccles, W.Foulkes, M.Genuardi, D.Goldgar, M.Greenblatt, R.Hofstra, F.Hogervorst, N.Hoogerbrugge, S.Plon, P.Radice, L.Rasmussen, O.Sinilnikova, A.Spurdle, and S.V.Tavtigian (2008).
Assessment of functional effects of unclassified genetic variants.
  Hum Mutat, 29, 1314-1326.  
18247379 J.Li, B.Warner, B.C.Casto, T.J.Knobloch, and C.M.Weghorst (2008).
Tumor suppressor p16(INK4A)/Cdkn2a alterations in 7, 12-dimethylbenz(a)anthracene (DMBA)-induced hamster cheek pouch tumors.
  Mol Carcinog, 47, 733-738.  
17881001 A.Mahajan, Y.Guo, C.Yuan, C.M.Weghorst, M.D.Tsai, and J.Li (2007).
Dissection of protein-protein interaction and CDK4 inhibition in the oncogenic versus tumor suppressing functions of gankyrin and P16.
  J Mol Biol, 373, 990.  
17370310 P.A.Chan, S.Duraisamy, P.J.Miller, J.A.Newell, C.McBride, J.P.Bond, T.Raevaara, S.Ollila, M.Nyström, A.J.Grimm, J.Christodoulou, W.S.Oetting, and M.S.Greenblatt (2007).
Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR).
  Hum Mutat, 28, 683-693.  
17486064 Y.C.Lin, M.B.Diccianni, Y.Kim, H.H.Lin, C.H.Lee, R.J.Lin, S.H.Joo, J.Li, T.J.Chuang, A.S.Yang, H.H.Kuo, M.D.Tsai, and A.L.Yu (2007).
Human p16gamma, a novel transcriptional variant of p16(INK4A), coexpresses with p16(INK4A) in cancer cells and inhibits cell-cycle progression.
  Oncogene, 26, 7017-7027.  
16596641 G.Interlandi, G.Settanni, and A.Caflisch (2006).
Unfolding transition state and intermediates of the tumor suppressor p16INK4a investigated by molecular dynamics simulations.
  Proteins, 64, 178-192.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
  17167857 M.Hocevar, M.Avbelj, B.Perić, J.Zgajnar, N.Besić, and T.Battelino (2006).
High prevalence of germline CDKN2A mutations in Slovenian cutaneous malignant melanoma families.
  Croat Med J, 47, 851-854.  
15899873 A.S.Chung, Y.J.Guan, Z.L.Yuan, J.E.Albina, and Y.E.Chin (2005).
Ankyrin repeat and SOCS box 3 (ASB3) mediates ubiquitination and degradation of tumor necrosis factor receptor II.
  Mol Cell Biol, 25, 4716-4726.  
16007099 B.Y.Choi, H.S.Choi, K.Ko, Y.Y.Cho, F.Zhu, B.S.Kang, S.P.Ermakova, W.Y.Ma, A.M.Bode, and Z.Dong (2005).
The tumor suppressor p16(INK4a) prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity.
  Nat Struct Mol Biol, 12, 699-707.  
14997555 B.A.Manjasetty, C.Quedenau, V.Sievert, K.Büssow, F.Niesen, H.Delbrück, and U.Heinemann (2004).
X-ray structure of human gankyrin, the product of a gene linked to hepatocellular carcinoma.
  Proteins, 55, 214-217.
PDB code: 1qym
15215520 C.H.Croy, S.Bergqvist, T.Huxford, G.Ghosh, and E.A.Komives (2004).
Biophysical characterization of the free IkappaBalpha ankyrin repeat domain in solution.
  Protein Sci, 13, 1767-1777.  
15153436 D.C.Chung (2004).
Cyclin D1 in human neuroendocrine: tumorigenesis.
  Ann N Y Acad Sci, 1014, 209-217.  
15612883 F.Zhang, L.Wang, P.P.Wu, Z.W.Yan, L.Zheng, Y.Y.Yu, and X.C.Jiang (2004).
In situ analysis of p16/INK4 promoter hypermethylation in esophageal carcinoma and gastric carcinoma.
  Chin J Dig Dis, 5, 149-155.  
15024004 T.Ito, Y.Hozumi, F.Sakane, S.Saino-Saito, H.Kanoh, M.Aoyagi, H.Kondo, and K.Goto (2004).
Cloning and characterization of diacylglycerol kinase iota splice variants in rat brain.
  J Biol Chem, 279, 23317-23326.  
12566564 A.Kohl, H.K.Binz, P.Forrer, M.T.Stumpp, A.Plückthun, and M.G.Grütter (2003).
Designed to be stable: crystal structure of a consensus ankyrin repeat protein.
  Proc Natl Acad Sci U S A, 100, 1700-1705.
PDB code: 1mj0
14506702 C.Kannengiesser, M.F.Avril, A.Spatz, K.Laud, G.M.Lenoir, and B.Bressac-de-Paillerets (2003).
CDKN2A as a uveal and cutaneous melanoma susceptibility gene.
  Genes Chromosomes Cancer, 38, 265-268.  
14621993 J.Li, S.H.Joo, and M.D.Tsai (2003).
An NF-kappaB-specific inhibitor, IkappaBalpha, binds to and inhibits cyclin-dependent kinase 4.
  Biochemistry, 42, 13476-13483.  
12517341 K.S.Tang, A.R.Fersht, and L.S.Itzhaki (2003).
Sequential unfolding of ankyrin repeats in tumor suppressor p16.
  Structure, 11, 67-73.  
14646619 M.Avbelj, M.Hocevar, K.Trebusak-Podkrajsek, C.Krzisnik, and T.Battelino (2003).
A novel L94Q mutation in the CDKN2A gene in a melanoma kindred.
  Melanoma Res, 13, 567-570.  
12009890 B.Zhang, and Z.Y.Peng (2002).
Structural consequences of tumor-derived mutations in p16INK4a probed by limited proteolysis.
  Biochemistry, 41, 6293-6302.  
11900540 J.Li, and M.D.Tsai (2002).
Novel insights into the INK4-CDK4/6-Rb pathway: counter action of gankyrin against INK4 proteins regulates the CDK4-mediated phosphorylation of Rb.
  Biochemistry, 41, 3977-3983.  
12352668 K.K.Yu, A.M.Zanation, J.R.Moss, and W.G.Yarbrough (2002).
Familial head and neck cancer: molecular analysis of a new clinical entity.
  Laryngoscope, 112, 1587-1593.  
12461329 W.G.Yarbrough (2002).
The ARF-p16 gene locus in carcinogenesis and therapy of head and neck squamous cell carcinoma.
  Laryngoscope, 112, 2114-2128.  
  11485924 J.Boström, B.Meyer-Puttlitz, M.Wolter, B.Blaschke, R.G.Weber, P.Lichter, K.Ichimura, V.P.Collins, and G.Reifenberger (2001).
Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas.
  Am J Pathol, 159, 661-669.  
11255261 M.J.Poi, T.Yen, J.Li, H.Song, J.C.Lang, D.E.Schuller, D.K.Pearl, B.C.Casto, M.D.Tsai, and C.M.Weghorst (2001).
Somatic INK4a-ARF locus mutations: a significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck.
  Mol Carcinog, 30, 26-36.  
11259469 R.Soni, T.O'Reilly, P.Furet, L.Muller, C.Stephan, S.Zumstein-Mecker, H.Fretz, D.Fabbro, and B.Chaudhuri (2001).
Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4.
  J Natl Cancer Inst, 93, 436-446.  
11579459 S.Auroy, M.F.Avril, A.Chompret, D.Pham, A.M.Goldstein, G.Bianchi-Scarrà, T.Frebourg, P.Joly, A.Spatz, C.Rubino, F.Demenais, and B.Bressac-de Paillerets (2001).
Sporadic multiple primary melanoma cases: CDKN2A germline mutations with a founder effect.
  Genes Chromosomes Cancer, 32, 195-202.  
  10892805 C.Yuan, T.L.Selby, J.Li, I.J.Byeon, and M.D.Tsai (2000).
Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data.
  Protein Sci, 9, 1120-1128.
PDB code: 1dc2
10651629 J.Li, M.J.Poi, D.Qin, T.L.Selby, I.J.Byeon, and M.D.Tsai (2000).
Tumor suppressor INK4: quantitative structure-function analyses of p18INK4C as an inhibitor of cyclin-dependent kinase 4.
  Biochemistry, 39, 649-657.  
10732752 N.Soufir, B.Bressac-de Paillerets, L.Desjardins, C.Lévy, J.Bombled, I.Gorin, P.Schlienger, and D.Stoppa-Lyonnet (2000).
Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, P14ARF or cdk4 genes.
  Br J Cancer, 82, 818-822.  
10611246 R.J.Lee, C.Albanese, M.Fu, M.D'Amico, B.Lin, G.Watanabe, G.K.Haines, P.M.Siegel, M.C.Hung, Y.Yarden, J.M.Horowitz, W.J.Muller, and R.G.Pestell (2000).
Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway.
  Mol Cell Biol, 20, 672-683.  
10409620 A.W.Ashton, G.Watanabe, C.Albanese, E.O.Harrington, J.A.Ware, and R.G.Pestell (1999).
Protein kinase Cdelta inhibition of S-phase transition in capillary endothelial cells involves the cyclin-dependent kinase inhibitor p27(Kip1).
  J Biol Chem, 274, 20805-20811.  
  10022885 B.B.McConnell, F.J.Gregory, F.J.Stott, E.Hara, and G.Peters (1999).
Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes.
  Mol Cell Biol, 19, 1981-1989.  
10410794 C.Wolberger (1999).
Multiprotein-DNA complexes in transcriptional regulation.
  Annu Rev Biophys Biomol Struct, 28, 29-56.  
10607671 J.A.Endicott, M.E.Noble, and J.A.Tucker (1999).
Cyclin-dependent kinases: inhibition and substrate recognition.
  Curr Opin Struct Biol, 9, 738-744.  
10074345 J.Li, I.J.Byeon, K.Ericson, M.J.Poi, P.O'Maille, T.Selby, and M.D.Tsai (1999).
Tumor suppressor INK4: determination of the solution structure of p18INK4C and demonstration of the functional significance of loops in p18INK4C and p16INK4A.
  Biochemistry, 38, 2930-2940.
PDB code: 1bu9
10431175 S.G.Sedgwick, and S.J.Smerdon (1999).
The ankyrin repeat: a diversity of interactions on a common structural framework.
  Trends Biochem Sci, 24, 311-316.  
10491434 W.G.Yarbrough, R.A.Buckmire, M.Bessho, and E.T.Liu (1999).
Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors.
  J Natl Cancer Inst, 91, 1569-1574.  
9794820 C.Wolberger (1998).
Combinatorial transcription factors.
  Curr Opin Genet Dev, 8, 552-559.  
9823374 M.Ruas, and G.Peters (1998).
The p16INK4a/CDKN2A tumor suppressor and its relatives.
  Biochim Biophys Acta, 1378, F115-F177.  
9782052 R.Baumgartner, C.Fernandez-Catalan, A.Winoto, R.Huber, R.A.Engh, and T.A.Holak (1998).
Structure of human cyclin-dependent kinase inhibitor p19INK4d: comparison to known ankyrin-repeat-containing structures and implications for the dysfunction of tumor suppressor p16INK4a.
  Structure, 6, 1279-1290.
PDB code: 1bd8
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.