Structure and Function of CLCA Proteins

Abstract

CLCA proteins were discovered in bovine trachea and named for a calcium-dependent chloride conductance found in trachea and in other secretory epithelial tissues. At least four closely located gene loci in the mouse and the human code for independent isoforms of CLCA proteins. Full-length CLCA proteins have an unprocessed mass ratio of ∼100 kDa. Three of the four human loci code for the synthesis of membrane-associated proteins. CLCA proteins affect chloride conductance, epithelial secretion, cell-cell adhesion, apoptosis, cell cycle control, mucus production in asthma, and blood pressure. There is a structural and probable functional divergence between CLCA isoforms containing or not containing β4-integrin binding domains. Cell cycle control and tumor metastasis are affected by isoforms with the binding domains. These isoforms are expressed prominently in smooth muscle, in some endothelial cells, in the central nervous system, and also in secretory epithelial cells. The isoform with disrupted β4-integrin binding (hCLCA1, pCLCA1, mCLCA3) alters epithelial mucus secretion and ion transport processes. It is preferentially expressed in secretory epithelial tissues including trachea and small intestine. Chloride conductance is affected by the expression of several CLCA proteins. However, the dependence of the resulting electrical signature on the expression system rather than the CLCA protein suggests that these proteins are not independent Ca2+-dependent chloride channels, but may contribute to the activity of chloride channels formed by, or in conjunction with, other proteins.

Proteomic approach to identify candidate effector molecules during the in vitro immune exclusion of infectiveTeladorsagia circumcinctain the abomasum of sheep

“…While intelectin has been previously implicated in immunity to nematodes [6], the demonstration of a secreted CLCA protein in response to parasite challenge is novel. CLCA proteins are putative Ca 2+ -activated Cl -channels or channel regulators but have also been shown to affect epithelial secretion, cell-cell adhesion, apoptosis, cell cycle control, and mucus production (for review, see [16,30]). hCLCA1 and mCLCA3 (alias gob-5) are distributed in mucin producing goblet cells [16].…”

“…CLCA proteins are putative Ca 2+ -activated Cl -channels or channel regulators but have also been shown to affect epithelial secretion, cell-cell adhesion, apoptosis, cell cycle control, and mucus production (for review, see [16,30]). hCLCA1 and mCLCA3 (alias gob-5) are distributed in mucin producing goblet cells [16]. Recent studies have shown that all subunits of hCLCA1 and mCLCA3 are secreted soluble proteins rather than being trans-membrane proteins [7,23].…”

Chlorine-35/37 NMR Spectroscopy of Solid Amino Acid Hydrochlorides: Refinement of Hydrogen-Bonded Proton Positions Using Experiment and Theory

“…16 Furthermore, interactions between chloride and various amino acid sidechains are responsible for chloride ion selectivity and transport in various ion channels including the ClC type. [17][18][19][20] The present study provides new insights into how the local chloride binding environment is manifested in the chlorine CS tensor.…”

“…16 Furthermore, interactions between chloride and various amino acid sidechains are responsible for chloride ion selectivity and transport in various ion channels including the ClC type. [17][18][19][20] The present study provides new insights into how the local chloride binding environment is manifested in the chlorine CS tensor.Another major thrust of the present work is to determine how sensitive the chlorine EFG and nuclear magnetic shielding tensors are to the local molecular structure surrounding the chloride ions, specifically the positions of the protons to which they are hydrogen-bonded. Ashbrook and Duer have recently described in detail how structural information may be extracted from solid-state NMR experiments performed on quadrupolar nuclei.…”

Expression of three distinct families of calcium-activated chloride channel genes in the mouse dorsal root ganglion

“…In the absence of specific pharmacological modulators, the identification of the ion channel(s) underlying this current is an important first step necessary for the development of tools designed to study this phenomenon. Members of three families of proteins have been shown to induce I Cl(Ca) when expressed in heterologous cellular systems: calcium-activated chloride channels (CLCAs), bestrophins and members of the tweety gene family (for reviews see [4,[7][8][9]16] ). In order to assess these molecules as candidates underlying sensory neuron I Cl(Ca) we analyzed expression of members of the 3 families by RT-PCR on normal and axotomized DRGs.…”