Mutant cancer protein STAT5b has two distinct conformational states.

Abstract

The point mutation N642H of the signal transducer and activator of transcription 5b (STAT5b) protein is linked to aggressive and drug resistant forms of cancer. While N642H is thought to promote cancer development by inducing constitutive STAT5b activity, the structural and dynamic underpinnings of the mutant's oncogenicity are not well understood. We apply extensive all-atom molecular dynamics simulations to all oligomeric forms of both wild type and N642H STAT5b to elucidate the structural and dynamic differences between the wild type and N642H mutant proteins. Our homology model of the phosphorylated STAT5b parallel dimer reveals a rigid, stable, and compact parallel dimer structure. Our simulations reveal several structural and dynamic similarities between the apo N642H mutant and phosphorylated parallel dimer. In particular, we observe two distinct states in the N642H mutant antiparallel dimer simulations, one of which has similar structure and dynamics to the phosphorylated parallel dimer, indicating that the N642H mutation may bias STAT5b toward a parallel-dimer-like conformation. The structural and dynamic information uncovered in this work contributes to our understanding of STAT5b hyperactivation by N642H and could help pave the way for strategies to overcome the drug resistance of this important mutation.