6pyx
Calcium Activated Chloride Channel Regulator 1 (CLCA1) VWA Domain
Structural highlights
FunctionCLCA1_HUMAN May be involved in mediating calcium-activated chloride conductance. May play critical roles in goblet cell metaplasia, mucus hypersecretion, cystic fibrosis and AHR. May be involved in the regulation of mucus production and/or secretion by goblet cells. Involved in the regulation of tissue inflammation in the innate immune response. May play a role as a tumor suppressor. Induces MUC5AC.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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-A 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 alpha3 and alpha4 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 alpha6 atypically extends from the VWA core. Finally, an analysis of TMEM16A structures suggests residues likely to mediate interaction with CLCA1 VWA. Structural and Biophysical Analysis of the CLCA1 VWA Domain Suggests Mode of TMEM16A Engagement.,Berry KN, Brett TJ Cell Rep. 2020 Jan 28;30(4):1141-1151.e3. doi: 10.1016/j.celrep.2019.12.059. Epub, 2020 Jan 28. PMID:31995732[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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