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Published online 8 October 2018
Detailed structural mapping of a channel reveals a molecular interaction that regulates calcium entry into cells.
Scientists from Weill Cornell Medicine-Qatar (WCM-Q) have found that the interaction of a protein complex with calcium channels makes them less available on the cell membrane, regulating the amount of calcium flowing into cells.
Calcium flow across the cell membrane is a dynamic process that regulates multiple physiological functions. Its disruption leads to a wide range of immunological, cardiac and neurological disorders.
Calcium entry and exit dynamics at the cell membrane are mediated through various channels and transporters. The Orai1 protein is a highly selective calcium channel whose function depends on the state of intracellular calcium stores.
Under normal conditions, Orai1 moves between the membrane and the inside of the cell. The molecular mechanism that regulates this movement has been poorly understood.
The WCM-Q team identified a protein complex, called chaperonin-containing T-complex protein 1 (CCT), that binds to a specific region on Orai1, making it less available at the cell membrane.1 Disruption of this interaction enriches its membrane presence. The CCT–Orai1 interaction represents a novel regulatory function for the CCT complex, originally identified as a regulator of protein folding, a process that affects protein function.
“The number of Orai1 channels at the cell membrane ultimately regulates the amount of calcium flowing into the cell, which in turn dictates a plethora of cellular functions, including gene transcription," says biophysicist Khaled Machaca from WCM-Q in Qatar.
“Further dissection of the molecular pathways regulating Orai1 trafficking will help elucidate multiple physiological processes and how they are deregulated in disease,” he adds.
Hodeify, R. et al. The CCT chaperonin is a novel regulator of Ca2+ signaling through modulation of Orai1 trafficking. Sci. Adv. 4: eaau1935 (2018).