Negatively charged, intrinsically disordered regions can accelerate target search by DNA-binding proteins

Xi Wang, Lavi S. Bigman, Harry M. Greenblatt, Binhan Yu, Yaakov Levy, Junji Iwahara

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

In eukaryotes, many DNA/RNA-binding proteins possess intrinsically disordered regions (IDRs) with large negative charge, some of which involve a consecutive sequence of aspartate (D) or glutamate (E) residues. We refer to them as D/E repeats. The functional role of D/E repeats is not well understood, though some of them are known to cause autoinhibition through intramolecular electrostatic interaction with functional domains. In this work, we investigated the impacts of D/E repeats on the target DNA search kinetics for the high-mobility group box 1 (HMGB1) protein and the artificial protein constructs of the Antp homeodomain fused with D/E repeats of varied lengths. Our experimental data showed that D/E repeats of particular lengths can accelerate the target association in the overwhelming presence of non-functional high-Affinity ligands ('decoys'). Our coarse-grained molecular dynamics (CGMD) simulations showed that the autoinhibited proteins can bind to DNA and transition into the uninhibited complex with DNA through an electrostatically driven induced-fit process. In conjunction with the CGMD simulations, our kinetic model can explain how D/E repeats can accelerate the target association process in the presence of decoys. This study illuminates an unprecedented role of the negatively charged IDRs in the target search process.

Original languageEnglish (US)
Pages (from-to)4701-4712
Number of pages12
JournalNucleic acids research
Volume51
Issue number10
DOIs
StatePublished - Jun 9 2023
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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