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Type: Journal article
Title: p21 exploits residue Tyr151 as a tether for high-affinity PCNA binding
Author: Kroker, A.
Bruning, J.
Citation: Biochemistry, 2015; 54(22):3483-3493
Publisher: American Chemical Society
Issue Date: 2015
ISSN: 0006-2960
Statement of
Alice J. Kroker and John B. Bruning
Abstract: Proliferating cell nuclear antigen (PCNA, processivity factor, sliding clamp) is a ring-shaped protein that tethers proteins to DNA in processes, including DNA replication, DNA repair, and cell-cycle control. Often used as a marker for cell proliferation, PCNA is overexpressed in cancer cells, making it an appealing pharmaceutical target. PCNA interacts with proteins through a PCNA interacting protein (PIP)-box, an eight-amino acid consensus sequence; di ff erent binding partners display a wide range of a ffi nities based on function. Of all biological PIP-boxes, p21 has the highest known a ffi nity for PCNA, allowing for inhibition of DNA replication and cell growth under cellular stress. As p21 is one of the few PIP-box sequences to contain a tyrosine rather than a phenylalanine in the eighth conserved position, we probed the signi fi cance of the hydroxyl group at this position using a mutational approach. Here we present the cocrystal structure of PCNA bound to a mutant p21 PIP-box peptide, p21Tyr151Phe, with associated isothermal titration calorimetry data. The p21Tyr151Phe peptide showed a 3-fold di ff erence in a ffi nity, as well as di ff erences in entropy and enthalpy of binding. These di ff erences can be attributed to a loss of hydrogen bonding capacity, as well as structural plasticity in the PCNA interdomain connector loop and the hydrophobic cavity of PCNA to which p21 binds. Thus, the hydroxyl group of Tyr151 in p21 acts as a tethering point for ideal packing and surface recognition of the peptide interface, increasing the binding a ffi nity of p21 for PCNA.
Keywords: Humans
Proliferating Cell Nuclear Antigen
Crystallography, X-Ray
Amino Acid Substitution
Protein Structure, Quaternary
Protein Structure, Tertiary
Protein Binding
Mutation, Missense
Cyclin-Dependent Kinase Inhibitor p21
Rights: © 2015 American Chemical Society
DOI: 10.1021/acs.biochem.5b00241
Appears in Collections:Aurora harvest 2
Molecular and Biomedical Science publications

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