小柯机器人

美国哥伦比亚大学Filippo Mancia、杜克大学David M. Virshup等研究人员合作揭示WLS/Evi介导Wnt转运和分泌的结构基础。这一研究成果于2020年12月23日在线发表在国际学术期刊《细胞》上。

研究人员表示，Wnt是进化保守的配体，可在短距离内发出信号来调节形态发生、细胞命运和干细胞更新。Wnt分泌的第一步和必不可少的步骤是它们的O-棕榈油酸化，随后将其装载到专用转运蛋白Wntless/evennessinterrupted（WLS/Evi）上。

研究人员报道了与WLS结合的棕榈油酸化人源WNT8A的3.2Å分辨率冷冻电镜（cryo-EM）结构。研究人员通过生化实验来探究了这些关联的生理意义。WLS膜结构域与G蛋白偶联受体（GPCR）具有紧密的结构同源性。Wnt发夹插入GPCR样结构域中保守的疏水腔中，并且棕榈油酸在两个螺旋之间突出进入双层。另一个Wnt发夹上高度保守残基的构象转换可能有助于其转移至接收细胞。这项工作为动物身体发育计划和干细胞生物学的主要机制提供了分子水平的见解。

附：英文原文

Title: Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion

Author: Rie Nygaard, Jia Yu, Jonathan Kim, Daniel R. Ross, Giacomo Parisi, Oliver B. Clarke, David M. Virshup, Filippo Mancia

Issue&Volume: 2020-12-23

Abstract: Wnts are evolutionarily conserved ligands that signal at short range to regulate morphogenesis,cell fate, and stem cell renewal. The first and essential steps in Wnt secretion aretheir O-palmitoleation and subsequent loading onto the dedicated transporter Wntless/evennessinterrupted (WLS/Evi). We report the 3.2 resolution cryogenic electron microscopy(cryo-EM) structure of palmitoleated human WNT8A in complex with WLS. This is accompaniedby biochemical experiments to probe the physiological implications of the observedassociation. The WLS membrane domain has close structural homology to G protein-coupledreceptors (GPCRs). A Wnt hairpin inserts into a conserved hydrophobic cavity in theGPCR-like domain, and the palmitoleate protrudes between two helices into the bilayer.A conformational switch of highly conserved residues on a separate Wnt hairpin mightcontribute to its transfer to receiving cells. This work provides molecular-levelinsights into a central mechanism in animal body plan development and stem cell biology.

DOI: 10.1016/j.cell.2020.11.038

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31610-X