Dimerization of p15RS mediated by a leucine zipper-like motif is critical for its inhibitory role on Wnt signaling.

We previously demonstrated that p15RS, a newly discovered tumor suppressor, inhibits Wnt/β-catenin signaling by interrupting the formation of β-catenin·TCF4 complex. However, it remains unclear how p15RS helps exert such an inhibitory effect on Wnt signaling based on its molecular structure. In this study, we reported that dimerization of p15RS is required for its inhibition on the transcription regulation of Wnt-targeted genes. We found that p15RS forms a dimer through a highly conserved leucine zipper-like motif in the coiled-coil terminus domain. In particular, residues Leu-248 and Leu-255 were identified as being responsible for p15RS dimerization, as mutation of these two leucines into prolines disrupted the homodimer formation of p15RS and weakened its suppression of Wnt signaling. Functional studies further confirmed that mutations of p15RS at these residues results in diminishment of its inhibition on cell proliferation and tumor formation. We therefore concluded that dimerization of p15RS governed by the leucine zipper-like motif is critical for its inhibition of Wnt/β-catenin signaling and tumorigenesis.