STAT3 SH2 Domain Aspartic Acid 661 Mutations Activate Immune Gene Programs.

ABSTRACT: The conserved aspartic acid residue D661 within the STAT3 SH2 domain is a recurrent mutational hotspot in hematologic malignancies, including T-cell large granular lymphocytic leukaemia, myelodysplastic syndromes and acute lymphoblastic leukaemia. To define the functional consequences of distinct STAT3^D661 variants, we integrated computational, structural and in vitro and in vivo genetic approaches. AlphaMissense and PolyPhen-2 classified all four STAT3^D661 variants (D661Y, D661V, D661N and D661H) as pathogenic. ClinVar classified D661Y and D661V as variants of uncertain significance. AlphaFold 3-based modelling predicted that D661Y and D661V strongly promoted SH2-TAD-mediated dimerization, while D661N and D661H exerted weaker structural effects. Functional in vitro a

SUBMITTER: Lee HK 

PROVIDER: S-EPMC12796846 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature