Title : Chemically induced proximity regulates protein function and degradation
Abstract:
Proximity, or the physical closeness of molecules, is a pervasive regulatory mechanism in biology. To understand the role of proximity in biologic mechanisms, chemical inducers of proximity (CIPs) or chemical inducers of dimerization (CIDs) were developed; these bifunctional small molecules bring two proteins in close proximity and subsequently enable precise temporal control of various cellular processes, such as cell signaling cascades, protein-protein interactions, cellular cargo transport, and genome editing. In this abstract, we are going to present three major types of CIP technologies our group have developed in recent years: i) nanobody-based CIP, or SNACIP, for regulation of intracellular protein functions (Nat. Commun. 2023); ii) autophagy-targeting nanobody chimera, or ATNC, for regulation of protein degradation (J. Am. Chem. Soc. 2023); and iii) photo-responsive CIPs, or chemo-optogenetic dimerization, for spatiotemporal control of protein functions by light (Angew. Chem. Int. Ed. 2018/ 2018). The first part is small molecule-nanobody conjugate induced proximity, or SNACIP, which was an integrated technology by combing 3 recent advancements from different fields, namely, i) CIP, ii) chemical nanobody engineering, and iii) cyclic arginine-rich peptide-based non-endocytic delivery system. As a nanobody-based CIP, SNACIP allows modulation of unligandable targets and endogenous intrinsically disordered proteins (IDPs), which represent challenging targets for traditional CIP/CID tools. The second part is ANTC technology, which uses nanobody-fused chimeras that recruit proteins to autophagy degradation pathway. Therefore, ATNC is able to degrade unligandable and undruggable proteins. The third part is chemo-optogenetic dimerization approaches which were developed by combing CIP concept and optogenetics. Chemo-optogenetic tools can be considered as a “Chemistry” version of optogenetics, exhibiting unique features and advantages. These examples showcased the important roles and great potentials of chemical induced proximity-based technologies for biology and medicine applications.
Audience Take-Away:
- The Presenter will present frontier chemically induced proximity-based tools for control of protein function, protein degradation and to regulate cellular activities by light. These tools will provide useful instructions for researchers in the related fields new means to study cellular functions and to degrade proteins for biological and biomedical purposes. The chemo-optogenetic dimerization approaches also offer photo-triggered dimerization tools for perturbation of cellular activities by light in a spatial and temporal manner.
