PDF(Pubmed)
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.
摘要：
Ca2激活的Cl-通道调节剂CLCA1通过直接接合细胞表面的通道来增强Ca2激活的Cl-通道（CaCC）TMEM16A的活性，抑制其再内化并增加Ca2依赖性Cl-电流（ICaCC）密度。我们现在提供了另外两个CLCA和TMEM16蛋白家族成员之间功能配对的证据，即CLCA4和CaCCTMEM16B。与CLCA1类似，（i）CLCA4是一种自切割金属蛋白酶，并且N末端部分（N-CLCA4）被分泌；（ii）N-CLCA4中的血管性血友病因子A型（VWA）结构域足以增强HEK293T细胞中的ICaCC；（iii）这是由VWA内的金属离子依赖性粘附位点基序介导的。结果表明,尽管CLCA1和CLCA4之间的保守调控机制和同源性，但CLCA4依赖性ICaCC由TMEM16B携带，而不是TMEM16A。我们的发现显示了CLCA/TMEM16相互作用的特异性，并表明这两个蛋白质家族之间存在广泛的生理和病理生理联系。
