Key result
The 2.0-Å crystal structure of human CLCA1 VWA bound to Ca2+ reveals a high-affinity open conformation of the MIDAS, suggesting how CLCA1 engages and potentiates the TMEM16A chloride channel.
Why the study?
The study was conducted to gain insight into the unique mechanism by which the CLCA1 VWA domain binds to and potentiates the TMEM16A channel.
The crystal structure of the CLCA1 VWA domain provides mechanistic insights into how it binds and potentiates the TMEM16A calcium-activated chloride channel.
Structural basis for CLCA1-TMEM16A engagement; leaves open translation to human physiology or disease.
The secreted protein calcium-activated chloride channel regulator 1 (CLCA1) utilizes a von Willebrand factor type A (VWA) domain to bind to and potentiate the calcium-activated chloride channel TMEM16A. To gain insight into this unique potentiation mechanism, we determined the 2.0-Å crystal structure of human CLCA1 VWA bound to Ca 2+ . The structure reveals the metal-ion-dependent adhesion site (MIDAS) in a high-affinity "open" conformation, engaging in crystal contacts that likely mimic how CLCA1 engages TMEM16A. The CLCA1 VWA contains a disulfide bond between α3 and α4 in close proximity to the MIDAS that is invariant in the CLCA family and unique in VWA structures. Further biophysical studies indicate that CLCA1 VWA is preferably stabilized by Mg 2+ over Ca 2+ and that α6 atypically extends from the VWA core. Finally, an analysis of TMEM16A structures suggests residues likely to mediate interaction with CLCA1 VWA.
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Berry et al. (2020) studied this question. The 2.0-Å crystal structure of human CLCA1 VWA bound to Ca2+ reveals a high-affinity open conformation of the MIDAS, suggesting how CLCA1 engages and potentiates the TMEM16A chloride channel.
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