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Review
. 2020 Apr 8;10(4):570.
doi: 10.3390/biom10040570.

Human PCNA Structure, Function and Interactions

Amaia González-Magaña  1 , Francisco J Blanco  1   2
Affiliations
Review

Human PCNA Structure, Function and Interactions

Amaia González-Magaña et al. Biomolecules. .

Abstract

: Proliferating cell nuclear antigen (PCNA) is an essential factor in DNA replication and repair. It forms a homotrimeric ring that embraces the DNA and slides along it, anchoring DNA polymerases and other DNA editing enzymes. It also interacts with regulatory proteins through a sequence motif known as PCNA Interacting Protein box (PIP-box). We here review the latest contributions to knowledge regarding the structure-function relationships in human PCNA, particularly the mechanism of sliding, and of the molecular recognition of canonical and non-canonical PIP motifs. The unique binding mode of the oncogene p15 is described in detail, and the implications of the recently discovered structure of PCNA bound to polymerase δ are discussed. The study of the post-translational modifications of PCNA and its partners may yield therapeutic opportunities in cancer treatment, in addition to illuminating the way PCNA coordinates the dynamic exchange of its many partners in DNA replication and repair.

Keywords: DNA repair; DNA replication; DNA sliding; PCNA; molecular recognition; protein interactions; structure.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The structure-based sequence alignment of DNA sliding clamps from H. sapiens, P. furiosus, E. coli, and the gp45 gene of bacteriophage T4. The alignment was performed with chain A from each of the PDB files, which corresponds to one of the three protomers (in the case of E. coli, which consists of two protomers, only the N-terminal two thirds of the sequence are shown). Similar residues are colored red. Secondary structure elements corresponding to human proliferating cell nuclear antigen (PCNA) are shown above the alignment, β-strands are indicated as arrows, α-helices as spirals, and β-turns as TT. The figure was generated with ESPript.
Figure 2
Figure 2
DNA sliding clamps from different organisms. The crystal structures of Homo sapiens PCNA (Protein Data Bank [PDB] code: 6GIS) bound to DNA, Pyrococcus furiosus PCNA (PDB code:1GE8), the Escherichia coli β clamp (PDB code: 3BEP) bound to DNA, and the gene 45 antigen of Bacteriophage T4 (PDB code: 1CZD). For each organism, the front (left) and side views (middle) of the three-dimensional crystal structure are shown. Each protomer is represented by a different color (blue, red and green). The surface electrostatic potential is represented, with positive potential depicted in blue and negative potential in red (right). The potential varies from −5KBT/e to +5KBT/e.
Figure 3
Figure 3
Human PCNA sliding along DNA. (A) Cogwheel diffusion mode: PCNA rotation tracks the DNA through a spiral motion, establishing transient interactions with DNA, which keeps the orientation of the clamp invariant relative to the DNA. The threefold rotation axis of PCNA around the DNA helical axis. In the lower panel, the evolution of PCNA–DNA contacts during cogwheel sliding is illustrated. Interacting side chains can rapidly and randomly switch between adjacent phosphates (indicated by the thin and thick lines), enabling PCNA to advance along the phosphate backbone by rotating and tilting motions. (B) Translational diffusion mode: PCNA travels along the DNA, without contacting the DNA. (Figure adapted from [28]).
Figure 4
Figure 4
The central region of p15 binds PCNA, while the N- and C-terminal tails remain disordered. (A) The crystal structure of a PCNA trimer bound to three p1541–72 fragments (PDB code: 6GWS) in cartoon representation. PCNA is colored in a different tone of green, while p15 fragments are shown in red. On the right, a zoom view of the binding interface is shown, where polar contacts between PCNA and p15 are marked by discontinuous yellow lines. p15 peptide and PCNA are represented by sticks and cartoons, respectively. Only those residues of PCNA that interact with p15 are drawn as sticks. The surface representation of the monomer of PCNA is shown with transparency. (B) A model of the full-length p15–PCNA complex. Front and side views of 10 modelled structures of the p15–PCNA complex based on experimental data. PCNA is shown as a gray surface and p15 as ribbons, with the central region colored in red, and the added disordered N- and C-terminal extensions colored in cyan and blue, respectively. In one of the 10 selected complex models, one p15 N-terminus folds back towards the front face of PCNA instead of passing through the hole.
Figure 5
Figure 5
Upper panel: Superposition of the structures of canonical (left) and non-canonical (right) PCNA-interacting motifs bound to PCNA. The PCNA protomers are represented by ribbons, and the peptides are represented by their Cα traces with different colors. Lower panel: Sequence alignment of PCNA-interacting protein fragments in crystal structures bound to PCNA. Consensus residues are highlighted in black, and the TD motif of the PCNA Interacting Protein box (PIP)-degron is depicted in red. The residues shown in the alignment are those observed in the crystal structure and do not include the terminal disordered residues present in the peptides.
Figure 6
Figure 6
Residues that suffer post-translational modifications (PTMs) mapped on the crystal structure of human PCNA (PDB code: 1VYM). The front (left) and back (right) faces of the PCNA protomer are shown in cartoon representation. The side chains of residues undergoing different post-translational modifications are depicted by sticks in different colors.
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