Wnts are short-range signaling proteins, expressed in all metazoans from sponges to humans, critical for cell development and fate. There are 19 different Wnts in the human genome with varying expression levels and patterns, and post-translational modifications. Common to essentially all Wnts is the palmitoleation of a conserved serine by the O-acyltransferase PORCN in the endoplasmic reticulum (ER). All lipidated Wnts then bind a dedicated carrier Wntless (WLS), endowed with the task of transporting them from the ER to the plasma membrane, and ultimately facilitating their release to receptors on the Wnt-receiving cell to initiate signaling. Here, we will focus on the WLS-mediated transport step. There are currently two published structures, both obtained by single-particle cryo-electron microscopy of the Wnt/WLS complex: human Wnt8A-bound and human Wnt3A-bound WLS. We analyze the two Wnt/WLS structures — remarkably similar despite the sequence similarity between Wnt8A and Wnt3A being only ∼39% — to begin to understand the conserved nature of this binding mechanism, and ultimately how one carrier can accommodate a family of 19 different Wnts. By comparing how Wnt associates with WLS with how it binds to PORCN and FZD receptors, we can begin to speculate on mechanisms of Wnt transfer from PORCN to WLS, and from WLS to FZD, thus providing molecular-level insight into these essential steps of the Wnt signaling pathway.

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