Differential conformational expansion of NUP98-HOXA9 oncoprotein from nanosized assemblies to macrophases

TL;DR

The paper studies how a cancer-related protein, NUP98-HOXA9, changes its structure across different assembly states, revealing insights into its role in gene regulation and cancer.

Contribution

The study reveals differential conformational expansion and micelle-like organization of the NUP98-HOXA9 oncoprotein across assembly states.

Findings

The FG domain of NUP98-HOXA9 exhibits different conformational compactness in monomeric, oligomeric, and densely packed condensate states.

The oligomeric state of NUP98-HOXA9 shows micelle-like organization with non-fixed stoichiometry and exposed DNA-binding domains.

Abstract

Transcription factors (TFs) play a central role in gene regulation by binding to specific DNA sequences and orchestrating the transcriptional machinery. A majority of eukaryotic TFs have a block copolymer architecture, with at least one block being a folded DNA interaction domain, and another block being highly enriched in intrinsic disorder. In this study, we focus on NUP98-HOXA9 (NHA9), a chimeric TF implicated in leukemogenesis. By integrating experiments and simulations, we examine the structural dynamics of NHA9’s FG domain across assembly states. We find that the FG domain has different conformational compactness in the monomeric, oligomeric, and densely packed condensate state. Notably, the oligomeric state exhibits micelle-like organization with non-fixed stoichiometry, with the DNA-binding domain exposed at the periphery. These findings offer molecular insight into the phase behaviour of NHA9 and highlight dynamic conformational transitions of intrinsically disordered regions during molecular assembly, with implications for understanding transcriptional regulation in cancer.

Some transcription factors can organize into different structural states, from small nanoscale clusters to macrophases. Here authors show that NHA9 undergoes differential conformational expansion across these states and exhibits micelle-like organization with non-fixed stoichiometry.

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