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Title: A small protein inhibits proliferating cell nuclear antigen by breaking the DNA clamp

Here, proliferating cell nuclear antigen (PCNA) forms a trimeric ring that encircles duplex DNA and acts as an anchor for a number of proteins involved in DNA metabolic processes. PCNA has two structurally similar domains (I and II) linked by a long loop (inter-domain connector loop, IDCL) on the outside of each monomer of the trimeric structure that makes up the DNA clamp. All proteins that bind to PCNA do so via a PCNA-interacting peptide (PIP) motif that binds near the IDCL. A small protein, called TIP, binds to PCNA and inhibits PCNA-dependent activities although it does not contain a canonical PIP motif. The X-ray crystal structure of TIP bound to PCNA reveals that TIP binds to the canonical PIP interaction site, but also extends beyond it through a helix that relocates the IDCL. TIP alters the relationship between domains I and II within the PCNA monomer such that the trimeric ring structure is broken, while the individual domains largely retain their native structure. Small angle X-ray scattering (SAXS) confirms the disruption of the PCNA trimer upon addition of the TIP protein in solution and together with the X-ray crystal data, provides a structural basis for the mechanism of PCNAmore » inhibition by TIP.« less
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [1] ;  [1]
  1. Univ. of Maryland and the National Institute of Standards and Technology, Rockville, MD (United States)
  2. Univ. of Maryland and the National Institute of Standards and Technology, Rockville, MD (United States); Third Institute of Oceanography, Fujian (China)
  3. Brookhaven National Lab. (BNL), Upton, NY (United States)
Publication Date:
Report Number(s):
BNL-112068-2016-JA
Journal ID: ISSN 0305-1048
Grant/Contract Number:
SC00112704
Type:
Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 44; Journal Issue: 13; Journal ID: ISSN 0305-1048
Publisher:
Oxford University Press
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; DNA replication; flap endonuclease 1; proliferating cell nuclear antigen
OSTI Identifier:
1340349

Altieri, Amanda S., Ladner, Jane E., Li, Zhuo, Robinson, Howard, Sallman, Zahur F., Marino, John P., and Kelman, Zvi. A small protein inhibits proliferating cell nuclear antigen by breaking the DNA clamp. United States: N. p., Web. doi:10.1093/nar/gkw351.
Altieri, Amanda S., Ladner, Jane E., Li, Zhuo, Robinson, Howard, Sallman, Zahur F., Marino, John P., & Kelman, Zvi. A small protein inhibits proliferating cell nuclear antigen by breaking the DNA clamp. United States. doi:10.1093/nar/gkw351.
Altieri, Amanda S., Ladner, Jane E., Li, Zhuo, Robinson, Howard, Sallman, Zahur F., Marino, John P., and Kelman, Zvi. 2016. "A small protein inhibits proliferating cell nuclear antigen by breaking the DNA clamp". United States. doi:10.1093/nar/gkw351. https://www.osti.gov/servlets/purl/1340349.
@article{osti_1340349,
title = {A small protein inhibits proliferating cell nuclear antigen by breaking the DNA clamp},
author = {Altieri, Amanda S. and Ladner, Jane E. and Li, Zhuo and Robinson, Howard and Sallman, Zahur F. and Marino, John P. and Kelman, Zvi},
abstractNote = {Here, proliferating cell nuclear antigen (PCNA) forms a trimeric ring that encircles duplex DNA and acts as an anchor for a number of proteins involved in DNA metabolic processes. PCNA has two structurally similar domains (I and II) linked by a long loop (inter-domain connector loop, IDCL) on the outside of each monomer of the trimeric structure that makes up the DNA clamp. All proteins that bind to PCNA do so via a PCNA-interacting peptide (PIP) motif that binds near the IDCL. A small protein, called TIP, binds to PCNA and inhibits PCNA-dependent activities although it does not contain a canonical PIP motif. The X-ray crystal structure of TIP bound to PCNA reveals that TIP binds to the canonical PIP interaction site, but also extends beyond it through a helix that relocates the IDCL. TIP alters the relationship between domains I and II within the PCNA monomer such that the trimeric ring structure is broken, while the individual domains largely retain their native structure. Small angle X-ray scattering (SAXS) confirms the disruption of the PCNA trimer upon addition of the TIP protein in solution and together with the X-ray crystal data, provides a structural basis for the mechanism of PCNA inhibition by TIP.},
doi = {10.1093/nar/gkw351},
journal = {Nucleic Acids Research},
number = 13,
volume = 44,
place = {United States},
year = {2016},
month = {5}
}