Effects of protein G-quadruplex interactions on phase transitions and protein aggregation

Abstract

AbstractWe show that human protein Znf706 interacts specifically with stable, non-canonical nucleic acid structures known as G-quadruplexes. Znf706, though only 76 residues long, is comprised of two distinct domains, one dis-ordered and one ordered. The disordered domain is homologous to the SERF family of proteins and acts to accelerate amyloid formation. The ordered domain contains a C2H2 type zinc-finger. We show that Znf706 not only accelerates amyloid formation but also accelerates amorphous protein aggregation. We find that Znf706 binds preferentially to parallel G-quadruplexes with low micromolar affinity, primarily using its N-terminus, whose dynamics are constrained upon interaction. G-quadruplexes are potent anti-aggregation agents, and their binding to Znf706 suppresses Znf706’s ability to accelerate protein aggregation and fibril formation. Znf706 in conjunction with G-quadruplexes thus may play a role in regulating protein folding. Depletion of Znf706 specifically impacts mRNA abundance of genes that contain high G-quadruplex density, implying that Znf706 may also serve as a G-quadruplex specific regulator. Our studies give insights into how proteins and G-quadruplexes interact, how these interactions affect both partners, lead to liquid-liquid phase transitions, and lead to the modulation of protein aggregation and cellular mRNA levels.