The PA207 Peptide Inhibitor of LIM-only Protein 2 (Lmo2) Targets Zinc Finger Domains in a Non-specific Manner

Peptide aptamers of LIM-only protein 2 (Lmo2) were previously used to successfully treat Lmo2-induced tumours in a mouse model of leukaemia. Here we show that the Lmo2 aptamer PA207, either as a free peptide or fused to thioredoxin Trx-PA207, causes purified Lmo2 to precipitate rather than binding to a defined surface on the protein. Stabilisation of Lmo2 through interaction with LIM domain binding protein 1 (Ldb1), a normal binding partner of Lmo2, abrogates this effect. The addition of free zinc causes Trx-PA207 to self associate, suggesting that PA207 destabilises Lmo2 by modulating normal zinc-coordination in the LIM domains. GST-pulldown experiments with other Lmo and Gata proteins indicates that PA207 can bind to a range of zinc finger proteins. Thus, PA207 and other cysteine-containing peptide aptamers for Lmo2 may form a class of general zinc finger inhibitors.