Synthetic antibodies to fine tune function of a cell membrane protein family, GPCR, an important drug target


04 Oct 2017

Synthetic antibodies to fine tune function of a cell membrane protein family, GPCR, an important drug target

 

By Dr Arun Shukla, Intermediate Fellow

IIT Kanpur

G protein-coupled receptors (GPCRs), a family of proteins embedded in the plasma membrane of the cells, regulate a broad range of physiological processes such as mood, memory, feeding and immune response. About half of the currently sold medicines including those prescribed for controlling the high blood pressure, treating heart failure, and to manage severe pain, work by activating or inactivating different receptors in the GPCR family.

A small class of scaffolding proteins, referred to as β-arrestins, critically govern the trafficking patterns, signaling and life-span of GPCRs via universally conserved cellular mechanisms. For example, β-arrestins drive GPCRs from the cell surface to cell interior upon activation, and it serves as one of the mechanisms to determine the temporal signaling response of these receptors. This particular function of β-arrestins depends on their ability to cross-talk with another cellular protein, called clathrin which is a key component of protein trafficking in the cell.

We have now generated synthetic proteins, antibody fragments to be precise, which can disrupt the β-arrestin-clathrin interaction, and thereby act as inhibitors of GPCR trafficking from the plasma membrane to endosomal vesicles, a process known as endocytosis or internalization. Importantly, these antibody fragments are highly selective for β-arrestin-clathrin interaction, and they do not interfere with other β-arrestin functions such as GPCR signaling. As GPCR trafficking patterns and underlying mechanisms are typically very well conserved, these antibody fragments based endocytosis inhibitors appear to be generic across the GPCR family.

Considering that some GPCR mutants are internalized even in the absence of their ligand stimulation, a situation that leads to pathophysiological conditions such as nephrogenic diabetes and retinitis pigmentosa, our antibody fragment based inhibitors have novel therapeutic potential. Moreover, the conceptual framework of this study should be applicable to other signaling systems as well, and it highlights the broad implications of our experimental strategy.   

A synthetic intrabody-based selective and generic inhibitor of GPCR endocytosis. Ghosh E, Srivastava A, Baidya M, Kumari P, Dwivedi H, Nidhi K, Ranjan R, Dogra S, Koide A, Yadav PN, Sidhu SS, Koide S, and Shukla AK. Nature Nanotechnology, October 2017