Microscopic view of a CLCA protein.

Unlocking the Secrets of CLCAs: How These Tiny Proteases Might Revolutionize Medicine

Beau Callahan in Science & Nature September 2025 • 4 min read.

"A deep dive into the intriguing world of CLCAs, exploring their potential impact on treating diseases from asthma to cancer and beyond."

In the vast and complex world of proteins, certain families stand out for their versatile roles and potential impact on human health. Among these, the zinc-dependent metalloproteases with the His-Glu-x-x-His (HExxH) active site motif, known as zincins, are a broad group of proteins involved in many metabolic and regulatory functions, found in all forms of life. These tiny molecular machines are not just structural components; they are key players in processes that keep us alive and functioning.

The human genome contains more than 100 genes encoding proteins with known zincin-like domains. A survey of all proteins containing the HExxH motif shows that approximately 52% of HExxH occurrences fall within known protein structural domains (as defined in the Pfam database). Domain families with a majority of members possessing a conserved HExxH motif include, not surprisingly, many known and putative metalloproteases. These proteases, initially recognized for their role in digestion, are now acknowledged for many crucial regulatory roles in cellular signaling in diverse biological processes, on cellular, tissue and organism scale, e.g. in cell proliferation and differentiation, inflammation, tissue remodelling, neurogenesis, angiogenesis, apoptosis, wound healing, blood coagulation.

This article will explore the fascinating CLCA family, a novel zincin-like protease with many cases of substituted active sites. We'll uncover their surprising connections to both human diseases and bacterial evolution, highlighting how these microscopic proteins could hold the key to future medical breakthroughs. This article will also touch on what is a protein domain and how are they identified.

What Makes CLCAs So Intriguing?

CLCAs, or Calcium-activated Chloride Channels, were initially believed to function as ion channels, controlling the flow of chloride ions across cell membranes. However, recent research has revealed that they are multifunctional proteins with a broader range of activities. These proteins have been implicated in several pathologies in humans, including asthma, chronic obstructive pulmonary disease (COPD) and cancer [24,25]. Originally, they were believed to be calcium-activated chloride channels [26,27]. Despite their characterisation as putative metalloproteases several years ago [28], they attracted moderate interest.

Here’s what makes them particularly interesting:

Dual Functionality: CLCAs can act as both ion channels and proteases (enzymes that break down proteins), giving them diverse roles in cellular processes.
Self-Cleavage: Several members of the CLCA family have been characterised beyond any doubt as secreted zinc-dependent metalloproteases that perform self-cleavage at a conserved site.
Involvement in Disease: CLCAs have been linked to various diseases, suggesting they play a role in disease development and progression. Vertebrates possess several closely homologous CLCA genes (usually 3-6), the functional relationships between them are not fully elucidated. It is not known whether CLCAs possess other physiological substrates except themselves, whether they are cleaved by other proteases except themselves, and whether different CLCA proteins cleave each other [32,33].
Surprising Evolutionary Connections: Recent studies have found CLCA homologues in bacteria and archaea, suggesting a potential case of horizontal gene transfer (HGT) from eukaryotes to prokaryotes. Recently, cases of patchy phylogenetic distribution of homologues of human genes in prokaryotes have attracted some attention, [9,10,23]. Such distribution has been interpreted as potential sign of horizontal gene transfer (HGT) [34-37].

These characteristics make CLCAs a hot topic for researchers seeking to understand the underlying mechanisms of various diseases and identify potential therapeutic targets.

The Future of CLCA Research

The study of CLCAs is still in its early stages, but the potential implications are vast. Further research is needed to fully elucidate the functions of CLCAs and their role in different diseases. By targeting CLCAs, scientists hope to develop new and effective therapies for a range of conditions, from respiratory illnesses to cancer.

About this Article -

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This article is based on research published under:

DOI-LINK: 10.1371/journal.pone.0062272, Alternate LINK

Title: Clcas - A Family Of Metalloproteases Of Intriguing Phylogenetic Distribution And With Cases Of Substituted Catalytic Sites

Subject: Multidisciplinary

Journal: PLoS ONE

Publisher: Public Library of Science (PLoS)

Authors: Anna Lenart, Małgorzata Dudkiewicz, Marcin Grynberg, Krzysztof Pawłowski

Published: 2013-05-09

Everything You Need To Know

What are CLCAs, and what makes them different from other ion channels?

Calcium-activated Chloride Channels, known as CLCAs, were initially thought to only function as ion channels controlling the flow of chloride ions across cell membranes. However, it has been discovered that CLCAs have dual functionality; they can act as both ion channels and proteases. Their diverse roles in cellular processes include self-cleavage at a conserved site and involvement in diseases such as asthma, COPD, and cancer. Further, surprising evolutionary connections have been found with CLCA homologues in bacteria and archaea.

What is the significance of the HExxH motif in zinc-dependent metalloproteases?

The HExxH motif is a specific amino acid sequence (Histidine-Glutamate-x-x-Histidine, where 'x' represents any amino acid) found in the active site of zinc-dependent metalloproteases known as zincins. This motif is crucial because it coordinates with a zinc ion, which is essential for the protease's catalytic activity. The zinc ion facilitates the breakdown of peptide bonds in proteins. Proteins with the HExxH motif are found in all forms of life and are involved in many metabolic and regulatory functions.

If CLCAs are linked to diseases like asthma and cancer, what are the potential therapeutic implications of this connection?

The potential therapeutic implications of studying CLCAs are vast, because they are implicated in several human diseases. By fully elucidating the functions of CLCAs, and their roles in diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cancer, it may be possible to develop new and effective therapies. Targeting CLCAs could open new avenues for treating conditions that currently lack satisfactory treatments. More research is required to fully understand all the physiological substrates for CLCAs.

How does horizontal gene transfer relate to the study of CLCAs, and what does it imply?

The concept of horizontal gene transfer (HGT) comes into play when considering CLCAs because scientists have discovered CLCA homologues in bacteria and archaea, which are typically found in eukaryotes. This suggests that CLCA genes may have been transferred from eukaryotes to prokaryotes through HGT. The patchy phylogenetic distribution of homologues of human genes in prokaryotes has attracted attention and has been interpreted as a potential sign of HGT. This raises questions about the evolutionary history and functional conservation of CLCAs across different domains of life.

What is a protein domain, and why is it important to identify protein domains in the study of proteins like CLCAs?

A protein domain is a distinct structural and functional unit within a protein. Domains are identified through sequence analysis and structural studies, often cataloged in databases like Pfam. The importance of identifying protein domains lies in understanding the modular nature of proteins, where each domain contributes specific functions, such as binding to other molecules or catalyzing reactions. Knowing the domain architecture of CLCAs helps in predicting their interactions and functions, including their role as proteases and potential interactions with other proteins or molecules in the cell.