Allosteric autoregulation of DNA binding via a DNA-mimicking protein domain: a biophysical study of ZNF410-DNA interaction using small angle X-ray scattering.
Nucleic Acids Res
; 51(4): 1674-1686, 2023 02 28.
Article
em En
| MEDLINE
| ID: mdl-36660822
ABSTRACT
ZNF410 is a highly-conserved transcription factor, remarkable in that it recognizes a 15-base pair DNA element but has just a single responsive target gene in mammalian erythroid cells. ZNF410 includes a tandem array of five zinc-fingers (ZFs), surrounded by uncharacterized N- and C-terminal regions. Unexpectedly, full-length ZNF410 has reduced DNA binding affinity, compared to that of the isolated DNA binding ZF array, both in vitro and in cells. AlphaFold predicts a partially-folded N-terminal subdomain that includes a 30-residue long helix, preceded by a hairpin loop rich in acidic (aspartate/glutamate) and serine/threonine residues. This hairpin loop is predicted by AlphaFold to lie against the DNA binding interface of the ZF array. In solution, ZNF410 is a monomer and binds to DNA with 11 stoichiometry. Surprisingly, the single best-fit model for the experimental small angle X-ray scattering profile, in the absence of DNA, is the original AlphaFold model with the N-terminal long-helix and the hairpin loop occupying the ZF DNA binding surface. For DNA binding, the hairpin loop presumably must be displaced. After combining biophysical, biochemical, bioinformatic and artificial intelligence-based AlphaFold analyses, we suggest that the hairpin loop mimics the structure and electrostatics of DNA, and provides an additional mechanism, supplementary to sequence specificity, of regulating ZNF410 DNA binding.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Nucleic Acids Res
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos