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The PCNA interaction motifs revisited: thinking outside the PIP-box.
- Source :
-
Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2019 Dec; Vol. 76 (24), pp. 4923-4943. Date of Electronic Publication: 2019 May 27. - Publication Year :
- 2019
-
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.
- Subjects :
- DNA genetics
DNA Repair genetics
DNA Replication genetics
DNA-Binding Proteins genetics
Humans
Intrinsically Disordered Proteins chemistry
Intrinsically Disordered Proteins genetics
Magnetic Resonance Spectroscopy
Proliferating Cell Nuclear Antigen genetics
Protein Conformation
Amino Acid Motifs genetics
DNA chemistry
DNA-Binding Proteins chemistry
Proliferating Cell Nuclear Antigen chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1420-9071
- Volume :
- 76
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Cellular and molecular life sciences : CMLS
- Publication Type :
- Academic Journal
- Accession number :
- 31134302
- Full Text :
- https://doi.org/10.1007/s00018-019-03150-0