9r18
Structure of Sortilin ECD in complex with TNFa-targeting SORTAC
Structural highlights
DiseaseSORT_HUMAN Note=A common polymorphism located in a non-coding region between CELSR2 and PSRC1 alters a CEBP transcription factor binding site and is responsible for changes in hepatic expression of SORT1. Altered SORT1 expression in liver affects low density lipoprotein cholesterol levels in plasma and is associated with susceptibility to myocardial infarction. FunctionSORT_HUMAN Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface. Required for protein transport from the Golgi apparatus to the lysosomes by a pathway that is independent of the mannose-6-phosphate receptor (M6PR). Also required for protein transport from the Golgi apparatus to the endosomes. Promotes neuronal apoptosis by mediating endocytosis of the proapoptotic precursor forms of BDNF (proBDNF) and NGFB (proNGFB). Also acts as a receptor for neurotensin. May promote mineralization of the extracellular matrix during osteogenic differentiation by scavenging extracellular LPL. Probably required in adipocytes for the formation of specialized storage vesicles containing the glucose transporter SLC2A4/GLUT4 (GLUT4 storage vesicles, or GSVs). These vesicles provide a stable pool of SLC2A4 and confer increased responsiveness to insulin. May also mediate transport from the endoplasmic reticulum to the Golgi.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedTargeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a powerful therapeutic strategy for degrading difficult-to-drug cytosolic proteins in the proteasome. Here, we present a strategy for extracellular TPD by reshaping the interaction between the lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation followed by endocytosis and target degradation. SORTAC activity can be genetically encoded, demonstrated by converting an IgG-binding nanobody to an IgG-degrading nanobody or by chemical conjugation, enabling conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, we generated PROTAC-like small molecule SORTACs with nanomolar range potency against two inflammatory proteins, the cytokine TNFa and the membrane protein vanin-1. Our results demonstrate that SORTACs constitute a modular platform for rapid generation of degraders of extracellular targets and with the potential to have wide impact in drug discovery. Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins.,Gustafsen C, Vilstrup J, Kristensen M, Koster D, Lende J, Larsen C, Simonsen A, Graversen A, Olsen D, Pallesen LT, Vaegter CB, Kresse JC, Schou M, Weyer K, Etzerodt A, Palmfeldt J, Kaas M, Qureshi O, Harrison N, Cowley J, Barnes N, Galland F, Naquet P, Mazarakis SMM, Greve D, Quattropani A, Glossop P, Whitlock G, Jensen KT, Nielsen SF, Madsen P, Glerup S Cell Chem Biol. 2026 Mar 27:S2451-9456(26)00072-3. doi: , 10.1016/j.chembiol.2026.03.002. PMID:41903545[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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