Editors' ChoiceStructural Biology

Different But Equal

Sci. Signal.  03 Feb 2009:
Vol. 2, Issue 56, pp. ec36
DOI: 10.1126/scisignal.256ec36

Binding of erythropoietin (Epo) to the erythropoietin receptor (EpoR) homodimer activates Janus kinase 2 (Jak2), which phosphorylates several tyrosine residues in EpoR. Phosphorylation of Tyr343 in EpoR recruits Stat5 (signal transducer and activator of transcription 5), which is phosphorylated by Jak2 and translocates to the nucleus to initiate gene expression. Because Epo is monomeric and asymmetrical, it binds to the two identical receptors in the EpoR homodimer using structurally distinct surfaces. Site 1 on Epo exhibits nanomolar affinity for EpoR, whereas site 2 displays micromolar affinity. To investigate whether binding of EpoR to the overlapping high- and low-affinity sites on Epo contributes equally to the initiation of downstream signaling, Zheng et al. designed and generated mutant EpoRs that could not bind site 1 (S1 EpoR) or site 2 (S2 EpoR) on Epo. As expected, cells expressing both mutated receptors, but not cells expressing only one mutant receptor, proliferated in response to Epo treatment, presumably because heterodimers of S1 EpoR and S2 EpoR were formed that could bind to both sites on Epo and initiate downstream signaling. The authors then introduced mutations that prevented binding of Jak2 or Stat5 to the receptor homodimer and expressed S1 and S2 EpoR heterodimers bearing these mutations in only one of the EpoR monomers. Epo-induced growth responses occurred when the mutations that abolished Jak2 binding to EpoR were present in only S1 EpoR or S2 EpoR, but not both. Similarly, heterodimers of S1 EpoR and S2 EpoR could support Epo-dependent cell proliferation and Stat5 activation, as long as there was one Tyr343 residue on an EpoR monomer. Thus, Zheng et al. propose that either monomer of the EpoR homodimer is capable of initiating downstream signaling, regardless of whether it binds to the high- or low-affinity site of Epo.

Y. L. Zhang, M. L. Radhakrishnan, X. Lu, A. W. Gross, B. Tidor, H. F. Lodish, Symmetric signaling by an asymmetric 1 erythropoietin: 2 erythropoietin receptor complex. Mol. Cell 33, 266–274 (2009). [Online Journal]