Recognition of a Key Anchor Residue by a Conserved Hydrophobic Pocket Ensures Subunit Interface Integrity in DNA Clamps

Senthil K. Perumal, Xiaojun Xu, Chunli Yan, Ivaylo Ivanov, Stephen J. Benkovic

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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, by monitoring the change in the fluorescence of a site-specifically labeled. 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 (molecular dynamic 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.

Original languageEnglish (US)
Pages (from-to)2493-2510
Number of pages18
JournalJournal of Molecular Biology
Volume431
Issue number14
DOIs
StatePublished - Jun 28 2019

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Structural Biology
  • Molecular Biology

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