Structure of the C-Terminal Region of p21WAF1/CIP1 Complexed with Human PCNA

The crystal structure of the human DNA polymerase delta processivity factor PCNA (proliferating cell nuclear antigen) complexed with a 22 residue peptide derived from the C-terminus of the cell-cycle checkpoint protein p21(WAF1/CIP1) has been determined at 2.6 angstrom resolution. p21 binds to PCNA in a 1:1 stoichiometry with an extensive array of interactions that include the formation of a beta sheet with the interdomain connector loop of PCNA. An intact trimeric ring is maintained in the structure of the p21-PCNA complex, with a central hole available for DNA interaction. The ability of p21 to inhibit the action of PCNA is therefore likely to be due to its masking of elements on PCNA that are required for the binding of other components of the polymerase assembly.

[1]  M. Nakanishi,et al.  The C-terminal Region of p21 Is Involved in Proliferating Cell Nuclear Antigen Binding but Does Not Appear to Be Required for Growth Inhibition (*) , 1995, The Journal of Biological Chemistry.

[2]  P. O'Connor,et al.  Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA. , 1995, Oncogene.

[3]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[4]  C. Sherr,et al.  D-type cyclins. , 1995, Trends in biochemical sciences.

[5]  S. Elledge,et al.  The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases , 1993, Cell.

[6]  A. Sancar,et al.  Purification of PCNA as a nucleotide excision repair protein. , 1992, Nucleic acids research.

[7]  I. Herskowitz,et al.  Joining the complex: Cyclin-dependent kinase inhibitory proteins and the cell cycle , 1994, Cell.

[8]  Anindya Dutta,et al.  A 39 amino acid fragment of the cell cycle regulator p21 is sufficient to bind PCNA and partially inhibit DNA replication in vivo. , 1996, Nucleic acids research.

[9]  G. Hannon,et al.  The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA , 1994, Nature.

[10]  S. Elledge,et al.  Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Bravo,et al.  Cloning and sequence of the human nuclear protein cyclin: homology with DNA-binding proteins. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Structure determination of plastocyanin from a specimen with a hemihedral twinning fraction of one-half. , 1993, Acta crystallographica. Section D, Biological crystallography.

[13]  John Kuriyan,et al.  Three-dimensional structure of the β subunit of E. coli DNA polymerase III holoenzyme: A sliding DNA clamp , 1992, Cell.

[14]  R. Wood,et al.  Proliferating cell nuclear antigen is required for DNA excision repair , 1992, Cell.

[15]  J. R. Smith,et al.  Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. , 1994, Experimental cell research.

[16]  James M. Roberts,et al.  Cloning of p27 Kip1 , a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals , 1994, Cell.

[17]  K. Sharp,et al.  Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons , 1991, Proteins.

[18]  A T Brünger,et al.  Slow-cooling protocols for crystallographic refinement by simulated annealing. , 1990, Acta crystallographica. Section A, Foundations of crystallography.

[19]  G. Hannon,et al.  Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair , 1994, Nature.

[20]  D. Bacon,et al.  A fast algorithm for rendering space-filling molecule pictures , 1988 .

[21]  Hui Zhang,et al.  D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA , 1992, Cell.

[22]  J. Maller,et al.  Cloning and characterization of the Xenopus cyclin-dependent kinase inhibitor p27XIC1. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[24]  Axel T. Brunger,et al.  X-PLOR Version 3.1: A System for X-ray Crystallography and NMR , 1992 .

[25]  Philip D. Jeffrey,et al.  Crystal structure of the p27Kip1 cyclin-dependent-kinase inibitor bound to the cyclin A–Cdk2 complex , 1996, Nature.

[26]  U. Hübscher,et al.  Mechanism of inhibition of proliferating cell nuclear antigen-dependent DNA synthesis by the cyclin-dependent kinase inhibitor p21. , 1995, Biochemistry.

[27]  G. Landberg,et al.  Determination of the epitope of an inhibitory antibody to proliferating cell nuclear antigen. , 1996, Experimental cell research.

[28]  B. Ducommun,et al.  Identification of binding domains on the p21Cip1 cyclin-dependent kinase inhibitor. , 1995, Oncogene.

[29]  J. Massagué,et al.  Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. , 1995, Genes & development.

[30]  R. Laskey,et al.  Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: Identification of a class of bipartite nuclear targeting sequence , 1991, Cell.

[31]  E. Ohtsuka,et al.  Structure-Function Relationship of the Eukaryotic DNA Replication Factor, Proliferating Cell Nuclear Antigen (*) , 1995, The Journal of Biological Chemistry.

[32]  C. Turck,et al.  Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit , 1993, Nature.

[33]  U. Strausfeld,et al.  Cip1 inhibits DNA replication but not PCNA-dependent nucleotide excision—repair , 1994, Current Biology.

[34]  P. Burgers,et al.  Molecular cloning, structure and expression of the yeast proliferating cell nuclear antigen gene. , 1990, Nucleic acids research.

[35]  D. Lane,et al.  A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen , 1995, Current Biology.

[36]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[37]  J. Massagué,et al.  Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1 , 1995, Nature.

[38]  S. Matsuoka,et al.  D-type cyclin-binding regions of proliferating cell nuclear antigen. , 1994, The Journal of biological chemistry.

[39]  P. O'Connor,et al.  Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. , 1994, Science.

[40]  Z. Kelman,et al.  Structural and functional similarities of prokaryotic and eukaryotic DNA polymerase sliding clamps. , 1995, Nucleic acids research.

[41]  G. Hannon,et al.  Subcellular distribution of p21 and PCNA in normal and repair-deficient cells following DNA damage , 1996, Current Biology.

[42]  L. Cox,et al.  Characterisation of the interaction between PCNA and Gadd45. , 1995, Oncogene.

[43]  John Kuriyan,et al.  Crystal structure of the eukaryotic DNA polymerase processivity factor PCNA , 1994, Cell.

[44]  Bert Vogelstein,et al.  Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21 , 1996, Nature.

[45]  M. Kirschner,et al.  Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA , 1995, Nature.

[46]  J. Hurwitz,et al.  Inhibition of Nucleotide Excision Repair by the Cyclin-dependent Kinase Inhibitor p21 (*) , 1995, The Journal of Biological Chemistry.