Structure of a CLC chloride ion channel by cryo-electron microscopy

Abstract

CLC proteins transport chloride (Cl−) ions across cellular membranes to regulate muscle excitability, electrolyte movement across epithelia, and acidification of intracellular organelles. Some CLC proteins are channels that conduct Cl− ions passively, whereas others are secondary active transporters that exchange two Cl− ions for one H+. The structural basis underlying these distinctive transport mechanisms is puzzling because CLC channels and transporters are expected to share the same architecture on the basis of sequence homology. Here we determined the structure of a bovine CLC channel (CLC-K) using cryo-electron microscopy. A conserved loop in the Cl− transport pathway shows a structure markedly different from that of CLC transporters. Consequently, the cytosolic constriction for Cl− passage is widened in CLC-K such that the kinetic barrier previously postulated for Cl−/H+ transporter function would be reduced. Thus, reduction of a kinetic barrier in CLC channels enables fast flow of Cl− down its electrochemical gradient. Some CLC proteins are channels that conduct chloride ions passively, whereas others are active co-transporters, a difference that has been hard to understand given their high degree of sequence homology; now, cryo-electron microscopy is used to determine the structure of a mammalian CLC channel, shedding light on this question. Some CLC proteins are channels that conduct chloride (Cl−) ions passively, whereas others are active co-transporters that exchange two Cl− ions for one H+. This functional difference has been hard to understand given their high degree of sequence homology. Now Roderick MacKinnon and colleagues have used cryo-electron microscopy to determine the structure of a mammalian CLC channel, CLC-K. Compared with CLC transporters, CLC-K has a cytosolic constriction for Cl− passage that is wider, thus reducing the kinetic barrier and enabling the fast flow of Cl− down its electrochemical gradient.

Cite this article

Park, E., Campbell, E. & MacKinnon, R. Structure of a CLC chloride ion channel by cryo-electron microscopy. Nature 541, 500–505 (2017). https://doi.org/10.1038/nature20812

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