The content describes the discovery and characterization of two new antibodies, 8M24 and 8G8, that bind to the carbohydrate recognition domain (CRD) of the human asialoglycoprotein receptor (ASGR) subunits ASGR1 and ASGR1/2, respectively. High-resolution crystal structures of the ASGR1:8M24 and ASGR2:8G8 complexes revealed that the antibodies bind to distinct epitopes on the receptors, away from the substrate binding site.
The authors demonstrate that fusion of the mutant RSPO2 (RSPO2RA) domain to these ASGR-targeting antibodies (8M24-RSPO2RA and 8G8-RSPO2RA) results in robust Wnt signaling enhancement in cell-based assays, similar to their previously described 4F3-RSPO2RA SWEETS molecule. This is achieved through the ASGR-mediated endocytosis and degradation of the E3 ubiquitin ligases ZNRF3 and RNF43, which are negative regulators of Wnt signaling.
Interestingly, the authors also found that the SWEETS molecules can induce the degradation of ASGR1 itself, through both proteasomal and lysosomal pathways. This is likely due to the SWEETS-mediated recruitment of E3 ligases to the proximity of ASGR1, leading to its ubiquitination and subsequent degradation. The ability to degrade ASGR1 may have therapeutic implications, as reduced ASGR1 levels have been associated with a lower risk of coronary artery disease.
Overall, the study demonstrates the versatility of the SWEETS platform, which can function as a targeted protein degradation system to modulate Wnt signaling in a tissue-specific manner, while also potentially offering an approach to eliminate the ASGR1 receptor.
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biorxiv.org
ข้อมูลเชิงลึกที่สำคัญจาก
by Sampathkumar... ที่ www.biorxiv.org 12-08-2023
https://www.biorxiv.org/content/10.1101/2023.12.08.570758v2สอบถามเพิ่มเติม