A cryptic symmetry switch allosterically controls how the PF4 self-protein turns into a pathogenic antigen.

The asymmetry of dimers-of-dimers formed by Platelet Factor 4 (PF4) renders this endogenous protein immunogenic, triggering autoimmune responses such as heparin-induced thrombocytopenia (HIT). Yet, the molecular basis of PF4 asymmetry has remained elusive. Here, we show that cryptic conformational switches control PF4 tetramer asymmetry and explain how a benign self-protein morphs into an immunogenic antigen, triggering a pathogenic autoimmune response. Mutations that target symmetry-switching sites stabilize a symmetric PF4 tetramer with markedly reduced affinity for HIT antibodies. These findings overturn the long-standing hypothesis that electrostatics alone drive PF4 asymmetry. Furthermore, stabilization of symmetric tetramers provides a conceptual framework for the robust conformational stratification of HIT antibodies, a persistent diagnostic challenge. Overall, our integrative model addresses key questions about the determinants of PF4 tetramer asymmetry and epitope exposure, suggesting a generalizable strategy for attenuating autoimmune responses by selectively stabilizing non‑immunogenic conformational states of self‑proteins rather than globally suppressing immunity.