The PCNA interaction motifs revisited: thinking outside the PIP-box

Research output: Contribution to journalJournal articleResearchpeer-review

Andreas Prestel, Nanna Wichmann, Joao M. Martins, Riccardo Marabini, Noah Kassem, Sebastian S. Broendum, Marit Otterlei, Olaf Nielsen, Martin Willemoës, Michael Ploug, Wouter Boomsma, Birthe B. Kragelund

Proliferating cell nuclear antigen (PCNA) is a cellular hub in DNA metabolism and a potential drug target. Its binding partners carry a short linear motif (SLiM) known as the PCNA-interacting protein-box (PIP-box), but sequence-divergent motifs have been reported to bind to the same binding pocket. To investigate how PCNA accommodates motif diversity, we assembled a set of 77 experimentally confirmed PCNA-binding proteins and analyzed features underlying their binding affinity. Combining NMR spectroscopy, affinity measurements and computational analyses, we corroborate that most PCNA-binding motifs reside in intrinsically disordered regions, that structure preformation is unrelated to affinity, and that the sequence-patterns that encode binding affinity extend substantially beyond the boundaries of the PIP-box. Our systematic multidisciplinary approach expands current views on PCNA interactions and reveals that the PIP-box affinity can be modulated over four orders of magnitude by positive charges in the flanking regions. Including the flanking regions as part of the motif is expected to have broad implications, particularly for interpretation of disease-causing mutations and drug-design, targeting DNA-replication and -repair.

Original languageEnglish
JournalCellular and Molecular Life Sciences
Number of pages21
ISSN1420-682X
DOIs
Publication statusE-pub ahead of print - 27 May 2019

ID: 225279131