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1h25

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Revision as of 06:45, 3 January 2018

CDK2/Cyclin A in complex with an 11-residue recruitment peptide from retinoblastoma-associated protein

Structural highlights

1h25 is a 5 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Related:	1ad6, 1gh6, 1gux, 1aq1, 1b38, 1b39, 1buh, 1ckp, 1di8, 1dm2, 1e1v, 1e1x, 1e9h, 1f5q, 1fin, 1fq1, 1fvt, 1fvv, 1g5s, 1gih, 1gii, 1gij, 1gy3, 1gz8, 1qmz
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[RB_HUMAN] Defects in RB1 are the cause of childhood cancer retinoblastoma (RB) [MIM:180200]. RB is a congenital malignant tumor that arises from the nuclear layers of the retina. It occurs in about 1:20'000 live births and represents about 2% of childhood malignancies. It is bilateral in about 30% of cases. Although most RB appear sporadically, about 20% are transmitted as an autosomal dominant trait with incomplete penetrance. The diagnosis is usually made before the age of 2 years when strabismus or a gray to yellow reflex from pupil ('cat eye') is investigated.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] Defects in RB1 are a cause of susceptibility to bladder cancer (BLC) [MIM:109800]. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Defects in RB1 are a cause of osteogenic sarcoma (OSRC) [MIM:259500].

Function

[RB_HUMAN] Key regulator of entry into cell division that acts as a tumor suppressor. Promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C. Acts as a transcription repressor of E2F1 target genes. The underphosphorylated, active form of RB1 interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, SUV420H1 and SUV420H2, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex (By similarity). In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity.^[14] [CCNA2_HUMAN] Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Progression through S phase of the eukaryotic cell cycle is regulated by the action of the cyclin dependent protein kinase 2 (CDK2) in association with cyclin A. CDK2/cyclin A phosphorylates numerous substrates. Substrate specificity often employs a dual recognition strategy in which the sequence flanking the phospho-acceptor site (Ser.Pro.X.Arg/Lys) is recognized by CDK2, while the cyclin A component of the complex contains a hydrophobic site that binds Arg/Lys.X.Leu ("RXL" or "KXL") substrate recruitment motifs. To determine additional sequence specificity motifs around the RXL sequence, we have performed X-ray crystallographic studies at 2.3 A resolution and isothermal calorimetry measurements on complexes of phospho-CDK2/cyclin A with a recruitment peptide derived from E2F1 and with shorter 11-mer peptides from p53, pRb, p27, E2F1, and p107. The results show that the cyclin recruitment site accommodates a second hydrophobic residue either immediately C-terminal or next adjacent to the leucine of the "RXL" motif and that this site makes important contributions to the recruitment peptide recognition. The arginine of the RXL motif contacts a glutamate, Glu220, on the cyclin. In those substrates that contain a KXL motif, no ionic interactions are observed with the lysine. The sequences N-terminal to the "RXL" motif of the individual peptides show no conservation, but nevertheless make common contacts to the cyclin through main chain interactions. Thus, the recruitment site is able to recognize diverse but conformationally constrained target sequences. The observations have implications for the further identification of physiological substrates of CDK2/cyclin A and the design of specific inhibitors.

Specificity determinants of recruitment peptides bound to phospho-CDK2/cyclin A.,Lowe ED, Tews I, Cheng KY, Brown NR, Gul S, Noble ME, Gamblin SJ, Johnson LN Biochemistry. 2002 Dec 31;41(52):15625-34. PMID:12501191^[15]

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

References

↑ Yandell DW, Campbell TA, Dayton SH, Petersen R, Walton D, Little JB, McConkie-Rosell A, Buckley EG, Dryja TP. Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling. N Engl J Med. 1989 Dec 21;321(25):1689-95. PMID:2594029
↑ Onadim Z, Hogg A, Baird PN, Cowell JK. Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6177-81. PMID:1352883
↑ Hogg A, Bia B, Onadim Z, Cowell JK. Molecular mechanisms of oncogenic mutations in tumors from patients with bilateral and unilateral retinoblastoma. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7351-5. PMID:8346255
↑ Cowell JK, Smith T, Bia B. Frequent constitutional C to T mutations in CGA-arginine codons in the RB1 gene produce premature stop codons in patients with bilateral (hereditary) retinoblastoma. Eur J Hum Genet. 1994;2(4):281-90. PMID:7704558
↑ Lohmann DR, Brandt B, Hopping W, Passarge E, Horsthemke B. Distinct RB1 gene mutations with low penetrance in hereditary retinoblastoma. Hum Genet. 1994 Oct;94(4):349-54. PMID:7927327
↑ Liu Z, Song Y, Bia B, Cowell JK. Germline mutations in the RB1 gene in patients with hereditary retinoblastoma. Genes Chromosomes Cancer. 1995 Dec;14(4):277-84. PMID:8605116
↑ Blanquet V, Turleau C, Gross-Morand MS, Senamaud-Beaufort C, Doz F, Besmond C. Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma. Hum Mol Genet. 1995 Mar;4(3):383-8. PMID:7795591
↑ Van Orsouw NJ, Li D, van der Vlies P, Scheffer H, Eng C, Buys CH, Li FP, Vijg J. Mutational scanning of large genes by extensive PCR multiplexing and two-dimensional electrophoresis: application to the RB1 gene. Hum Mol Genet. 1996 Jun;5(6):755-61. PMID:8776589
↑ Lohmann DR, Gerick M, Brandt B, Oelschlager U, Lorenz B, Passarge E, Horsthemke B. Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma. Am J Hum Genet. 1997 Aug;61(2):282-94. PMID:9311732 doi:10.1086/514845
↑ Mateu E, Sanchez F, Najera C, Beneyto M, Castell V, Hernandez M, Serra I, Prieto F. Genetics of retinoblastoma: a study. Cancer Genet Cytogenet. 1997 May;95(1):40-50. PMID:9140452
↑ Yilmaz S, Horsthemke B, Lohmann DR. Twelve novel RB1 gene mutations in patients with hereditary retinoblastoma. Mutations in brief no. 206. Online. Hum Mutat. 1998;12(6):434. PMID:10671068 doi:<434::AID-HUMU15>3.0.CO;2-A 10.1002/(SICI)1098-1004(1998)12:6<434::AID-HUMU15>3.0.CO;2-A
↑ Klutz M, Horsthemke B, Lohmann DR. RB1 gene mutations in peripheral blood DNA of patients with isolated unilateral retinoblastoma. Am J Hum Genet. 1999 Feb;64(2):667-8. PMID:9973307 doi:10.1086/302254
↑ Yu YS, Kim IJ, Ku JL, Park JG. Identification of four novel RB1 germline mutations in Korean retinoblastoma patients. Hum Mutat. 2001 Sep;18(3):252. PMID:11524739 doi:10.1002/humu.1184
↑ Ren S, Rollins BJ. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell. 2004 Apr 16;117(2):239-51. PMID:15084261
↑ Lowe ED, Tews I, Cheng KY, Brown NR, Gul S, Noble ME, Gamblin SJ, Johnson LN. Specificity determinants of recruitment peptides bound to phospho-CDK2/cyclin A. Biochemistry. 2002 Dec 31;41(52):15625-34. PMID:12501191

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1h25"

@@ Line 1: / Line 1: @@
-==CDK2/CYCLIN A IN COMPLEX WITH AN 11-RESIDUE RECRUITMENT PEPTIDE FROM RETINOBLASTOMA-ASSOCIATED PROTEIN==
+==CDK2/Cyclin A in complex with an 11-residue recruitment peptide from retinoblastoma-associated protein==
 <StructureSection load='1h25' size='340' side='right' caption='[[1h25]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
@@ Line 5: / Line 6: @@
 </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ad6|1ad6]], [[1gh6|1gh6]], [[1gux|1gux]], [[1aq1|1aq1]], [[1b38|1b38]], [[1b39|1b39]], [[1buh|1buh]], [[1ckp|1ckp]], [[1di8|1di8]], [[1dm2|1dm2]], [[1e1v|1e1v]], [[1e1x|1e1x]], [[1e9h|1e9h]], [[1f5q|1f5q]], [[1fin|1fin]], [[1fq1|1fq1]], [[1fvt|1fvt]], [[1fvv|1fvv]], [[1g5s|1g5s]], [[1gih|1gih]], [[1gii|1gii]], [[1gij|1gij]], [[1gy3|1gy3]], [[1gz8|1gz8]], [[1qmz|1qmz]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h25 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h25 OCA], [http://pdbe.org/1h25 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h25 RCSB], [http://www.ebi.ac.uk/pdbsum/1h25 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h25 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h25 OCA], [http://pdbe.org/1h25 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h25 RCSB], [http://www.ebi.ac.uk/pdbsum/1h25 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1h25 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 15: / Line 16: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h2/1h25_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h2/1h25_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 32: / Line 33: @@
 ==See Also==
-*[[Cyclin|Cyclin]]
-*[[Cyclin-dependent kinase|Cyclin-dependent kinase]]
 *[[User:Iris To/Retinoblastoma Protein Regulation|User:Iris To/Retinoblastoma Protein Regulation]]
 == References ==

1h25

From Proteopedia

Revision as of 06:45, 3 January 2018

CDK2/Cyclin A in complex with an 11-residue recruitment peptide from retinoblastoma-associated protein

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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