A sulfotyrosine motif in the human TrkB extracellular domain is required for activation by the agonist antibody ZEB85.

A sulfotyrosine modification at residue 400 in the human TrkB extracellular juxtamembrane domain is required for ZEB85 antibody binding and activation of TrkB signaling.

• Why it matters: TrkB is central to synaptic plasticity and neuroprotection, but BDNF delivery is difficult and ZEB85 offers a selective alternative whose mechanism needed clarification.
• What they did: The ZEB85 binding site was mapped to the TrkB extracellular juxtamembrane region, and structures of ZEB85 and BDNF bound to their sites were determined; binding- and activation-deficient TrkB mutants were tested for ligand sequestration in cultured human neurons.
• The result: BDNF binding extends into the juxtamembrane domain but does not require sulfotyrosine 400 for TrkB activation, explaining how BDNF can displace ZEB85 via an overlapping epitope.

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