Recognition of a Key Anchor Residue by a Conserved Hydrophobic Pocket Ensures Subunit Interface Integrity in DNA Clamps
| Autor: | Xiao-Jun Xu, Stephen J. Benkovic, Senthil K. Perumal, Ivaylo Ivanov, Chunli Yan |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
Protein Conformation DNA damage Protein subunit Molecular Dynamics Simulation Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Replication factor C Structural Biology Proliferating Cell Nuclear Antigen Humans Protein Interaction Maps Replication Protein C Molecular Biology 030304 developmental biology 0303 health sciences DNA clamp biology Chemistry DNA replication DNA Proliferating cell nuclear antigen Protein Subunits Clamp Mutation Mutagenesis Site-Directed Biophysics biology.protein Hydrophobic and Hydrophilic Interactions 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | J Mol Biol |
| ISSN: | 0022-2836 |
| DOI: | 10.1016/j.jmb.2019.04.035 |
| Popis: | Sliding clamp proteins encircle duplex DNA and are involved in processive DNA replication and the DNA damage response. Clamp proteins are ring-shaped oligomers (dimers or trimers) and are loaded onto DNA by an ATP-dependent clamp-loader complex that ruptures the interface between two adjacent subunits. Here we measured the solution dynamics of the human clamp protein Proliferating Cell Nuclear Antigen (PCNA) by monitoring the change in the fluorescence of a site-specifically labeled PCNA protein construct. To unravel the origins of clamp subunit interface stability, we carried out comprehensive comparative analysis of the interfaces of seven sliding clamps. We used computational modeling (MD simulations and MM/GBSA binding energy decomposition analyses) to identify conserved networks of hydrophobic residues critical for clamp stability and ring-opening dynamics. The hydrophobic network is shared among clamp proteins and exhibits a “key in a keyhole” pattern where a bulky aromatic residue from one clamp subunit is anchored into a hydrophobic pocket of the opposing subunit. Bioinformatics and dynamic network analyses showed that this oligomeric latch is conserved across DNA sliding clamps from all domains of life and dictates the dynamics of clamp opening and closing. |
| Databáze: | OpenAIRE |
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