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

We 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 disordered 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.