Wnt proteins are a class of protein signaling molecules that bind to WLS proteins within the cell, and only with the help of the transporter WLS can Wnt be secreted into the extracellular environment and then bind to receptors on the surface of the target cell membrane (Figure 1).
If the Wnt protein is compared to a key, the matching membrane receptor is a lock, and through the combination of the two, a series of cascades of reactions within the unlocked target cell can be activated and the signal is transmitted to the nucleus to regulate the expression of related genes. The Wnt signaling pathway is highly conserved in multicellular animals and plays an important regulatory role in many important life processes, such as early embryonic development, individual growth, maintenance of adult tissue homeostasis, and stem cell self-renewal. Mutations in some genes in the Wnt signaling pathway will cause abnormal signal transduction activity, leading to a variety of human diseases, including malignant tumors.
Figure 1. Secretion of Wnt and binding to receptors on the surface of cell membranes. a. WLS-dependent pathway of Wnt protein secretion; Wnt proteins secreted outside the cell bind to receptors on the cell membrane and activate downstream signaling pathways.
The secretion of the Wnt protein is key to the activation of downstream signaling pathways, but the molecular mechanism of the process is not well understood due to the lack of accurate three-dimensional structural information about the relevant protein.
On July 27, 2021, the Martin Research Group of the School of Life Sciences of Westlake University and the Zhou Qiang Research Group of the School of Life Sciences of Westlake University published a research paper entitled Cryo-EM structure of human Wntless in complex with Wnt3a in the Journal of Nature Communications online.
The paper reports the high-resolution cryo-EM structure of the human-derived Wnt transporter Wntless (WLS) with the Wnt3a complex 2.2 angstroms.
Zhou Qiang's research group of Ma Dan's research group used single-particle cryo-EM technology to obtain the three-dimensional structure of the human Wnt transporter WLS and Wnt3a complex, Wnt3a is the most widely studied Wnt protein in the field of Wnt signaling pathway, and this achievement will play an important role in promoting research in the field. In addition, cryo-EM data processing of small molecular weight and asymmetrical membrane proteins has been a difficult point in the field of cryo-EM research, in which they broke through the technical bottleneck and finally obtained an accurate three-dimensional structural model with an overall resolution of up to 2.2 angstroms.
The structure shows that three main binding regions are formed between WLS and Wnt3a (Figure 2a), and the interaction within these binding regions is critical to the binding of WLS to Wnt3a, the secretion of Wnt3a, and the activation of the downstream signaling pathway of Wnt3a through biochemical and functional experiments. Amino acid sequences in the interaction region are highly conserved in different Wnt and WLS (Figure 2b), suggesting that WLS-mediated Wnt secretion has a conserved molecular mechanism.
Figure 2. WLS-Wnt3a complex 3D structural model. a. WLS-Wnt3a overall three-dimensional structure and interaction interface; Sequence conservatization analysis of different structural regions of WLS and Wnt3a.
The research results reveal the molecular basis of WLS-mediated Wnt secretion, which can help better understand the transmission of Wnt signaling molecules and the mechanism of signaling pathway activation, which is an important progress in the field of Wnt signaling pathway research. At the same time, the high-resolution and precise structural model obtained in this study will also provide important clues for the development of anti-tumor drugs for the Wnt secretion pathway.
Ma Dan and Zhou Qiang, distinguished researchers of the School of Life Sciences of Westlake University, are the co-corresponding authors of this article. Zhong Qing, a doctoral student at Westlake University, Zhao Yanyu, a postdoctoral fellow, Ye Fangfei, a research assistant, and Xiao Zaiyu, a doctoral student, are the co-first authors of this paper.
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Martin's research group uses a variety of biophysical methods such as cryo-EM and X-ray crystal diffraction to study the three-dimensional structure of proteins and protein complexes closely related to major human diseases (such as tumors), and combines biochemical and cell biology methods to study the molecular mechanisms of important biological processes in the tumor microenvironment. The research group has long recruited postdoctoral and scientific research assistants with backgrounds in biochemistry, cell biology and structural biology, as well as experience in animal experiments.
Please submit your resume to: [email protected].
Thesis Link:
https://www.nature.com/articles/s41467-021-24731-3
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