钙激活氯离子通道调节剂 4（CLCA4）对人细胞中 TMEM16B 通道活性的调节。

Modulation of TMEM16B channel activity by the calcium-activated chloride channel regulator 4 (CLCA4) in human cells.

机构信息

Center for the Investigation of Membrane Excitability Diseases (CIMED), Washington University School of Medicine, Saint Louis, Missouri, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, Missouri, USA.

Division of Pulmonary and Critical Care, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.

出版信息

J Biol Chem. 2024 Jul;300(7):107432. doi: 10.1016/j.jbc.2024.107432. Epub 2024 May 31.

DOI:10.1016/j.jbc.2024.107432

PMID:38825009

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11231702/

Abstract

The Ca-activated Cl channel regulator CLCA1 potentiates the activity of the Ca-activated Cl channel (CaCC) TMEM16A by directly engaging the channel at the cell surface, inhibiting its reinternalization and increasing Ca-dependent Cl current (I) 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 I 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 I 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

钙激活氯离子通道调节剂 CLCA1 通过在细胞表面直接与通道结合，抑制其再内化并增加钙激活氯离子通道（CaCC）TMEM16A 的活性，从而增强其活性。我们现在提供了另外两个 CLCA 和 TMEM16 蛋白家族成员，即 CLCA4 和 CaCC TMEM16B 之间功能配对的证据。与 CLCA1 相似，（i）CLCA4 是一种自切割金属蛋白酶，其 N 端部分（N-CLCA4）被分泌；（ii）N-CLCA4 中的血管性血友病因子 A（VWA）结构域足以在 HEK293T 细胞中增强 I；（iii）这是通过 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 之间存在保守的调节机制和同源性，但 CLCA4 依赖性 I 由 TMEM16B 而不是 TMEM16A 携带。我们的发现表明 CLCA/TMEM16 相互作用具有特异性，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学联系。