Designer proteins that can tweak cellular gate-keeping

Reasearchers at IIT Kanpur have designed synthetic proteins that can selectively interrupt certain functions inside the human cell, making them a potential new therapeutic tool for many

diseases1. These synthetic proteins (antibodies) selectively interrupt a cellular pathway involved in pulling ‘receptors’ inside the cell and restricting them to the cell membrane, says lead

researcher Arun Shukla. The new proteins give an edge over conventional tools such as siRNA or CRISPR-CAS which deplete the protein levels, and remove all their functions across the board.

The designer proteins, on the other hand, can selectively block one specific function i.e. receptor ‘endocytosis’ while not affecting the others such as receptor signaling, he adds. Inside

human cells, a family of gatekeepers called G protein-coupled receptors (GPCRs), are crucial for a broad range of physiological functions including brain functions, human behaviours and

cardiovascular regulation. “About half of the currently sold medicines, for example those prescribed for controlling high blood pressure, treating heart failure, and to manage severe pain,

work by activating or inactivating these receptors,” Shukla says. Typically, these receptors travel inside the cell after binding their signal, a process that is referred to as receptor

endocytosis. Subsequently, these receptors are either degraded or sent back to the membrane. This serves as a mechanism for cells to dampen the signaling response. The new synthetic proteins

localise the receptors in the membrane, from where they continue to signal. Considering that some GPCRs are internalised even in the absence of their signals, a situation that leads to

pathophysiological conditions such as nephrogenic diabetes, these designer proteins can also be developed into novel therapeutics, the researchers say.