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Understanding CLIC proteins

- Wits University

Health Awareness Month: Dr Sadhna Mathura is excavating the hidden potential of chloride intracellular channel (CLIC) proteins in the human body.

Mathura, a Claude Leon Research Fellow at the Protein Structure Function Research Unit (PSFRU) at Wits, says CLIC proteins are commonly associated with vertebrates and found within most of our vital organs such as the heart, brain and muscles.

Most proteins are either soluble or insoluble within a cell.

What makes CLIC proteins different is the fact that under certain conditions they can change their state from soluble to insoluble, enabling them to oscillate between the cytoplasm of a cell and the cell membrane.

“This useful ability has earned these enigmatic compounds the stage-name, the ‘chameleon proteins’,” says Mathura.

Her project focuses on the human CLIC4 protein. The work may have remarkable implications for the treatment of various diseases precipitated by cell death and toxicity, such as cancer, Alzheimer’s and Parkinson’s.

“If we can understand what causes these proteins to undergo these ‘spontaneous’ conformational changes and thus protein unfolding, we may be able to understand the impact it has on these diseases,” explains Mathura.

Her plan of action is to pin down and exploit the precise conditions that facilitate the not-so-spontaneous structural changes of CLIC proteins. Being typically localised in the membrane, certain cellular stress inducers can cause the protein to move into the nucleus.

Recent work has shown that one such stress inducer is the presence of nitric oxide in the cell and this has been implicated in the translocation of CLIC4 from the membrane into the nucleus. Nitric oxide attaches to the CLIC4 protein by a process called S-nitrosation thereby modifying the protein’s structure.

“Broadly speaking, we aim to synthesise, purify and characterise the human CLIC4 protein using methods previously attempted by Littler and co-workers. Thereafter, we would need to identify the sites where S-nitrosation is likely to occur on the CLIC4 protein.”

Mathura’s strategy is to modify the site on the CLIC4 protein where S-nitrosation occurs, using site-directed mutagenesis and then compare this protein to an unmodified CLIC4 in terms of structure and function.

“If we find out exactly how it works, how it moves in and out, then we can begin to understand its role in cancer and some neuro-degenerative diseases,” says Mathura. 

Mathura completed her BSc Honours and MSc (cum laude) degrees at the University of Natal before moving to Wits in 2005. Here she completed her PhD in Bioinorganic Chemistry, working on vitamin B12 and related compounds. Two papers have been published from her PhD work. She is currently hosted at the PSFRU by Professor Heini Dirr.