A Combination of Bio‐Orthogonal Supramolecular Clicking and Proximity Chemical Tagging as a Supramolecular Tool for Discovery of Putative Proteins Associated with Laminopathic Disease

Abstract

AbstractProtein mutations alter protein–protein interactions that can lead to a number of illnesses. Mutations in lamin A (LMNA) have been reported to cause laminopathies. However, the proteins associated with the LMNA mutation have mostly remained unexplored. Herein, a new chemical tool for proximal proteomics is reported, developed by a combination of proximity chemical tagging and a bio‐orthogonal supramolecular latching based on cucurbit[7]uril (CB[7])‐based host–guest interactions. As this host–guest interaction acts as a noncovalent clickable motif that can be unclicked on‐demand, this new chemical tool is exploited for reliable detection of the proximal proteins of LMNA and its mutant that causes laminopathic dilated cardiomyopathy (DCM). Most importantly, a comparison study reveals, for the first time, mutant‐dependent alteration in LMNA proteomic environments, which allows to identify putative laminopathic DCM‐linked proteins including FOXJ3 and CELF2. This study demonstrates the feasibility of this chemical tool for reliable proximal proteomics, and its immense potential as a new research platform for discovering biomarkers associated with protein mutation‐linked diseases.