Multidirectional Activity Control of Cellular Processes by a Versatile Chemo‐optogenetic Approach

• Published in: Angewandte Chemie International Edition 2018-09, Vol.57 (37), p.11993-11997
• Main Authors: Chen, Xi, Venkatachalapathy, Muthukumaran, Dehmelt, Leif, Wu, Yao‐Wen
• Format: Article
• Language: English
• Subjects: Antibiotics; chemo-optogenetics; Communication; Communications; Dimerization; HeLa Cells; Humans; Intracellular signalling; intracellular transport; Ligands; Light; Microscopy, Confocal; multidirectional activity; Optogenetics - methods; Organelles; Organic chemistry; Peroxisomes - metabolism; photoactivated; Proteins; rac1 GTP-Binding Protein - chemistry; rac1 GTP-Binding Protein - metabolism; signaling; Tacrolimus Binding Proteins - chemistry; Tacrolimus Binding Proteins - metabolism; Tacrolimus-binding protein; Trimethoprim; Trimethoprim - chemistry; Trimethoprim - metabolism
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201806976

The spatiotemporal dynamics of proteins or organelles plays a vital role in controlling diverse cellular processes. However, acute control of activity at distinct locations within a cell is challenging. A versatile multidirectional activity control (MAC) approach is presented, which employs a photoactivatable system that may be dimerized upon chemical inducement. The system comprises second‐generation SLF*‐TMP (S*T) and photocaged NvocTMP‐Cl dimerizers; where, SLF*‐TMP features a synthetic ligand of the FKBP(F36V) binding protein, Nvoc is a caging group, and TMP is the antibiotic trimethoprim. Two MAC strategies are demonstrated to spatiotemporally control cellular signaling and intracellular cargo transport. The novel platform enables tunable, reversible, and rapid control of activity at multiple compartments in living cells. Multidirectional activity control allows spatiotemporal control of cellular signaling and intracellular cargo transport. Tunable, reversible, and rapid control of activity for proteins of interest (POI) at distinct locations within a living cell is made possible by photoactivatable, dual, chemically induced dimerization through a synthetic ligand and a photocaged dimerizer.