Abstract

The Ca2+-activated Cl channel regulator CLCA1 potentiates the activity of the Ca2+-activated Cl channel (CaCC) TMEM16A by directly engaging the channel at the cell surface, inhibiting its reinternalization and increasing Ca2+-dependent Cl current (ICaCC) density. We now present evidence of functional pairing between two other CLCA and TMEM16 protein family members, namely CLCA4 and the CaCC TMEM16B. Similar to CLCA1, (i) CLCA4 is a self-cleaving metalloprotease, and the N-terminal portion (N-CLCA4) is secreted; (ii) the von Willebrand factor type A (VWA) domain in N-CLCA4 is sufficient to potentiate ICaCC in HEK293T cells; and (iii) this is mediated by the metal ion-dependent adhesion site motif within VWA. The results indicate that, despite the conserved regulatory mechanism and homology between CLCA1 and CLCA4, CLCA4-dependent ICaCC are carried by TMEM16B, rather than TMEM16A. Our findings show specificity in CLCA/TMEM16 interactions and suggest broad physiological and pathophysiological links between these two protein families.

Original languageEnglish
Article number107432
JournalJournal of Biological Chemistry
Volume300
Issue number7
DOIs
StatePublished - Jul 2024

Keywords

  • CLCA family
  • TMEM16 family
  • calcium-activated chloride channel
  • calcium-activated chloride channel regulator
  • von Willebrand factor type A domain

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