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

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

doi:10.1007/s00018-019-03150-0

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

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

20 Citations (Scopus)

Abstract

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 language	English
Journal	Cellular and Molecular Life Sciences
Volume	76
Issue number	24
Pages (from-to)	4923-4943
Number of pages	21
ISSN	1420-682X
DOIs	https://doi.org/10.1007/s00018-019-03150-0
Publication status	Published - 1 Dec 2019

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title = "The PCNA interaction motifs revisited: thinking outside the PIP-box",

abstract = "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.",

author = "Andreas Prestel and Nanna Wichmann and Martins, {Joao M.} and Riccardo Marabini and Noah Kassem and Broendum, {Sebastian S.} and Marit Otterlei and Olaf Nielsen and Martin Willemo{\"e}s and Michael Ploug and Wouter Boomsma and Kragelund, {Birthe B.}",

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T1 - The PCNA interaction motifs revisited

T2 - thinking outside the PIP-box

AU - Prestel, Andreas

AU - Wichmann, Nanna

AU - Martins, Joao M.

AU - Marabini, Riccardo

AU - Kassem, Noah

AU - Broendum, Sebastian S.

AU - Otterlei, Marit

AU - Nielsen, Olaf

AU - Willemoës, Martin

AU - Ploug, Michael

AU - Boomsma, Wouter

AU - Kragelund, Birthe B.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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DO - 10.1007/s00018-019-03150-0

M3 - Journal article

C2 - 31134302

SN - 1420-682X

VL - 76

SP - 4923

EP - 4943

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

IS - 24

ER -

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

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