Synthetic self-localizing ligands that control the spatial location of proteins in living cells.
Small-molecule ligands that control the spatial location of proteins in living cells would be valuable tools for regulating biological systems. However, the creation of such molecules remains almost unexplored because of the lack of a design methodology. Here we introduce a conceptually new type of synthetic ligands, self-localizing ligands (SLLs), which spontaneously localize to specific subcellular regions in mammalian cells. We show that SLLs bind their target proteins and relocate (tether) them rapidly from the cytoplasm to their targeting sites, thus serving as synthetic protein translocators. SLL-induced protein translocation enables us to manipulate diverse synthetic/endogenous signaling pathways. The method is also applicable to reversible protein translocation and allows control of multiple proteins at different times and locations in the same cell. These results demonstrate the usefulness of SLLs in the spatial (and temporal) control of intracellular protein distribution and biological processes, opening a new direction in the design of small-molecule tools or drugs for cell regulation.
Top Runner Incubation Center for Academia-Industry Fusion, Nagaoka University of Technology, 1603-1 Kamitomioka, Nagaoka, Niigata 940-2188, Japan.
Manabu
M
Ishida
Hideaki
H
Watanabe
Kazumasa
K
Takigawa
Yasutaka
Y
Kurishita
Choji
C
Oki
Akinobu
A
Nakamura
Itaru
I
Hamachi
Shinya
S
Tsukiji
D000818:Animals; D004926:Escherichia coli / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D021381:Protein Transport / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
D008024:Ligands; D054852:Small Molecule Libraries; D013762:Tetrahydrofolate Dehydrogenase; D022061:Tacrolimus Binding Protein 1A