HOMODIMERIZATION RESTORES BIOLOGICAL-ACTIVITY TO AN INACTIVE ERYTHROPOIETIN MUTANT

Erythropoietin (Epo) is believed to transduce a signal by bringing two Epo receptors into close proximity, enabling cross-phosphorylation. W e compared monomeric Epos with homodimers in which two Epo monomers ar e linked by polyglycine. Monomeric Epo mutant R103A is unable to suppo rt Epo-dependent cell growth or trigger Janus kinase 2 and STATE activ ation, even at concentrations greater than 7,000 times that sufficient for wildtype Epo activity. In contrast, R103A homodimer induces proli feration and transduces signal at concentrations similar to that of wi ld-type Epo monomer and homodimer. These experiments show that two dis crete domains on Epo are required for receptor binding and activation. Our results also suggest that the EpoR can be dimerized by different forms and sizes of molecules, as long as two recognition moths are pro vided in the same molecule. Design of other dimeric molecules may enha nce our understanding of cytokine specificity and signal transduction.