Recombinant Human Lefty-A Protein

Lefty was first identified in a screen for undifferentiated cell-specific cDNAs from the P19 mouse embryonal carcinoma cells. Its mRNA expression on the left side of the developing embryo earned the name “Lefty”. The human orthologue was initially identified as Ebaf, Endometrial Bleeding-Associated Factor. Two genes exist in mouse (Lefty-1 and Lefty-2) and two in humans (Lefty-A and Lefty-B). By amino acid sequence, human Lefty-A and -B are more similar to each other (96%) than to either Lefty-1 or -2 in the mouse (81 - 82% identical). Lefty contains the six cysteine residues that are conserved among TGF-beta related proteins and that are necessary to form the cysteine-knot structure. However, Lefty is distinct from other family members in that it has two RXXR cleavage sites, a longer carboxy terminal sequence, and it lacks the cysteine residue required for intermolecular disulfide linkage. Thus, mature forms of Lefty are larger than mature forms of other TGF-beta -related proteins.

Lefty homologues have been identified in other vertebrate organisms including chick, frog, and zebrafish. Although the amino acid sequence identity is not well conserved among vertebrate species, the expression pattern of Lefty on the left side is well conserved. Furthermore its function in patterning left-right asymmetry of the developing organ systems such as the heart and lung is consistent in all vertebrate species examined. Lefty acts as an antagonist to Nodal signaling, potentially by competing for binding to a common receptor.