TY - JOUR
T1 - Modulation of TMEM16B channel activity by the calcium-activated chloride channel regulator 4 (CLCA4) in human cells
AU - Sala-Rabanal, Monica
AU - Yurtsever, Zeynep
AU - Berry, Kayla N.
AU - McClenaghan, Conor
AU - Foy, Alyssa J.
AU - Hanson, Alex
AU - Steinberg, Deborah F.
AU - Greven, Jessica A.
AU - Kluender, Colin E.
AU - Alexander-Brett, Jennifer M.
AU - Nichols, Colin G.
AU - Brett, Tom J.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/7
Y1 - 2024/7
N2 - 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.
AB - 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.
KW - CLCA family
KW - TMEM16 family
KW - calcium-activated chloride channel
KW - calcium-activated chloride channel regulator
KW - von Willebrand factor type A domain
UR - http://www.scopus.com/inward/record.url?scp=85196400376&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2024.107432
DO - 10.1016/j.jbc.2024.107432
M3 - Article
C2 - 38825009
AN - SCOPUS:85196400376
SN - 0021-9258
VL - 300
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 7
M1 - 107432
ER -