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Medientyp:
E-Artikel
Titel:
Negatively charged, intrinsically disordered regions can accelerate target search by DNA-binding proteins
Beteiligte:
Wang, Xi;
Bigman, Lavi S;
Greenblatt, Harry M;
Yu, Binhan;
Levy, Yaakov;
Iwahara, Junji
Erschienen:
Oxford University Press (OUP), 2023
Erschienen in:
Nucleic Acids Research, 51 (2023) 10, Seite 4701-4712
Sprache:
Englisch
DOI:
10.1093/nar/gkad045
ISSN:
0305-1048;
1362-4962
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p>