Zinc Fingers 10 and 11 of Miz-1 undergo conformational exchange to achieve specific DNA binding

Olivier Boisvert; Danny Létourneau; Patrick Delattre; Cynthia Tremblay; Émilie Jolibois; Martin Montagne; Pierre Lavigne

doi:10.1016/j.str.2021.12.001

Zinc Fingers 10 and 11 of Miz-1 undergo conformational exchange to achieve specific DNA binding

Structure. 2022 Apr 7;30(4):623-636.e5. doi: 10.1016/j.str.2021.12.001. Epub 2021 Dec 27.

Authors

Olivier Boisvert¹, Danny Létourneau¹, Patrick Delattre¹, Cynthia Tremblay¹, Émilie Jolibois¹, Martin Montagne¹, Pierre Lavigne²

Affiliations

¹ Département de biochimie et de génomique fonctionnelle, Institut de Pharmacologie de Sherbrooke and PROTÉO, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, 3001 12 Avenue N, Sherbrooke, Quebec J1H 5N4, Canada.
² Département de biochimie et de génomique fonctionnelle, Institut de Pharmacologie de Sherbrooke and PROTÉO, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, 3001 12 Avenue N, Sherbrooke, Quebec J1H 5N4, Canada. Electronic address: pierre.lavigne@usherbrooke.ca.

PMID: 34963061
DOI: 10.1016/j.str.2021.12.001

Abstract

Miz-1 (ZBTB17) is a poly-zinc finger BTB/POZ transcription factor with 12 consecutive C2H2 zinc fingers (ZFs) that binds transcriptional start sites (TSSs) to regulate the expression of genes involved in cell development and proliferation. As of now, it is not known which of the 12 consecutive ZFs are responsible for the recognition of the 24 base pair consensus sequence found at these TSSs. Evidence suggests ZFs 7-12 plays this role. We provide validation for this and describe the structural and dynamical characterization of unprecedented conformational exchange in the linker between ZFs 10 and 11. This conformational exchange uncouples ZFs 7-10 from 11 and 12 and promotes a scanning-recognition mechanism through which the two segments cooperate to bind two sub-sites at both ends of the consensus. We further show that this can result in the coiling of TSSs as part of Miz-1's mechanism of transcriptional transactivation.

Keywords: C2H2 Zinc Fingers; Conformational Exchange; DNA Binding; Miz-1; Molecular Recognition; NMR.

MeSH terms

Amino Acid Sequence
Binding Sites
DNA / metabolism
Gene Expression Regulation
Kruppel-Like Transcription Factors
Transcription Factors* / metabolism
Zinc Fingers*

Substances

Kruppel-Like Transcription Factors
Transcription Factors
DNA