An autoregulation of DNA binding model of ZNF410 revealed by biophysical study of small-angle X-ray scattering

Conference: 2022: 72nd ACA Annual Meeting
Gundeep Kaur Poster Author
MD ANDERSON CANCER CENTER
HOUSTON, TX 
 
Ren Ren Additional Author
MD Anderson
 
Michal Hammel Additional Author
LBNL
Berkeley, CA 
 
John Horton Additional Author
MD Anderson Cancer Center of The University of Texas
Houston, TX 
 
Robert Bluementhal Additional Author
The University of Toledo College of Medicine and Life Sciences
Toledo, OH 
 
Xing Zhang Additional Author
The University of Texas -M.D. Anderson Cancer Center
Houston, TX 
 
Xiaodong Cheng Additional Author
The University of Texas -M.D. Anderson Cancer Center
Houston, TX 
 
07/30/2022: 5:30 PM - 7:30 PM
Poster Session 
Portland Marriott Downtown Waterfront 
Room: Exhibit Hall 

Description

ZNF410 is a unique and remarkable transcription factor in that it recognizes a 15-base pair DNA element but has only one single target gene in the mammalian genome in erythroid cells. ZNF410 is composed of uncharacterized N- and C-terminal domains with a tandem array of ordered five zinc fingers (ZFs). Unexpectedly, full-length ZNF410 has reduced DNA binding affinity, compared to that of isolated DNA binding ZF array. AlphaFold predicts a partially folded N-terminal subdomain including a 30-residue long helix and its proceeding hairpin loop, which is rich in acidic (aspartate/glutamate) and serine/threonine residues. The hairpin loop is placed into the DNA binding interface of the ZF array. In solution, ZNF410 is a monomer and binds to DNA in 1:1 stoichiometry. Surprisingly, the single best-fit model from 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 interface. Upon the DNA binding, the hairpin loop must be displaced. By using a combination of biophysical, biochemical, bioinformatic and artificial intelligence-based AlphaFold approaches, we suggest that the hairpin loop might mimic the structure and electrostatics of DNA, and provides an additional mechanism, in supplementary to the sequence specificity, to regulate the DNA binding of ZNF410.