Structural determination of CALHM channels
EMSL Project ID
51238
Abstract
The calcium homeostasis modulators (CALHMs) are one of the key ATP release channel families,consisting of three members, CALHM1, 2 and 3. They are voltage-dependent, extracellular, calciumconcentration regulated, nonselective ion channels that are permeable to the signaling molecules ATP and calcium. Highly expressed in the brain and taste buds, CALHM channels play essential roles in taste and neuron transmission, and their dysregulation has been associated with various neurological disorders including Alzheimer disease ischemic brain damage, and depression, making CALHM channels important pharmacological targets.
We have published strong evidence that CALHM2 is undecameric and exists as both
hemichannels and gap junctions in vitro (Choi et al. Nature, online on Nov. 27th 2019). We have
determined cryo-EM structures of human CALHM2 in the Ca2+-free open state, and ruthenium red-bound inhibited state in detergent. These preliminary results provide not only the first atomic structures of a CALHM family member, but also the first bona fide structure in an inhibited state, which has never been
reported for channels with similar topology including connexins, pannexins, innexins and VRACs
(volume-regulated anion channels).
Building on this preliminary data, we propose to continue the structural studies of CALHM2 and
the other two family members, CALHM1 and CALHM3. We aim to define the molecular basis for a
comprehensive gating mechanism, the molecular determinants of gap junction formation, determine the
structures of CALHM1, 2 and 3 in native-like lipid environment (SMA polymer), and define ligand binding
sites to understand pharmacology of CALHM channels. These advances will provide a solid foundation
for developing new drugs against neurodegenerative diseases and for a deeper understanding of the
function of the ATP release channel family.
Project Details
Start Date
2020-01-15
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Co-Investigator(s)
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