DNA is a linear chain of nucleotides, portions of which are faithfully transcribed into linear messenger RNA. The message in this RNA is translated into strings of amino acids - proteins. Proteins need to take a precise three-dimensional shape to become functional entities. This protein folding does not happen all by itself, at least most of the time. A special bunch of proteins called molecular chaperones assist in correctly folding the protein.
The idea of chaperones may sound quaint and Victorian, but in biological systems they play crucial roles. After the new protein chain has been shaped correctly, chaperones move on. Or else the new chain is eliminated. Without chaperones, newly synthesised proteins would soon become a tangled mess of insoluble aggregates, hindering cellular processes.
Many molecular chaperones belong to the class of heat shock proteins (or stress-response proteins). This is because whenever an organism is subjected to elevated temperatures a heat shock proteins in the system begin to lose their native shapes, and chaperones are produced in large quantities to restore order.
Chaperones are needed under physiological conditions too, for normal cellular function.
Misfolding of proteins can cause a number of diseases. Alpha-synuclein protein, present in neurons, is wrongly folded in Parkinson's disease. Brains of Alzheimer's patients have plaques formed from aggregates of amyloid beta-peptide. This accumulation of amyloid fibrils is toxic, leading to widespread destruction of neurons a 'neurodegenerative disorder. Aberrant folding of crystallins of the eye lens leads to cataract. In the eye lens, an abundant subset of proteins called alpha-crystallins themselves serve as chaperones a single R116G mutation in human alpha crystallin is responsible for autosomal dominant congenital cataract.
Major chaperones in humans include HSP70, HSC70 and HSP90: the numbers express the size of the proteins in kilodaltons. In normal cells 1%2% of all proteins present are heat shock proteins. This number rises threefold during stressful conditions.
HSP70 is induced by heat, whereas HSC70 is always present at high levels in normal cells. HSC70 appears to be more like a molecular thermometer, with an ability to sense cold temperatures. This knowledge comes from the study of an intriguing set of disorders, exemplified by Familial Cold Autoinflammatory Syndrome (FCAS). Symptoms of these disorders include rashes on the skin, pain in joints and fever. Periodic episodes may last from a few hours to a few weeks. These episodes begin early in life, the trigger being exposure to cold, or a stress such as fatigue. The confusing set of symptoms shown in this rare disorder make diagnosis difficult it often takes ten years from first clinical presentation to a confirmed diagnosis.
The first family with confirmed FCAS in India was reported only in August this year. Sagar Bhattad and colleagues, at the Aster CMI Hospital in Bengaluru, traced the genetic underpinnings of FCAS in a four-year old boy who frequently suffered from winter rashes. It turns out that several family members, including his paternal great-grandfather, had similar symptoms. This was published in Indian Journal of Pediatrics, August 2021, 88(8):834.
Addressing the role of HSC70 in sensing low temperatures, the group of Ghanshyam Swarup at the Centre for Cellular and Molecular Biology has worked out a framework for the triggering of autoinflammatory conditions This was published in The FEBS Journal, 2021; doi:10.1111/febs.16203. Disorders related to cold sensitivity are caused by mutations in proteins that regulate inflammation. At normal body temperatures, HSC70 is able to coax these mutated proteins to fold correctly and thus function normally. In cold conditions, however, the HSC70 molecule is itself slightly altered in its shape and is not able to unerringly interact with the mutated regulators of inflammation. This leads to a pathological state with symptoms such as chills, joint pains and rich red skin rashes setting in within two hours.
Cancer cells divide at break-neck pace, and heat shock proteins are very important in maintaining the stressful cancerous state. An overabundance of heat shock proteins in cancer cells is an indicator of a poor prognosis. Cancerous cells accumulate mutations in proteins that would normally suppress tumours. HSP70 and HSP90 play the roles of villains, as they continue to fold the mutated proteins, thus allowing tumour progression. In the laboratory, inhibitors of HSP90 have shown much promise as anti-cancer agents. However, no inhibitor has yet been approved for human use, as the levels required for these to be effective are too toxic for your body.
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Heat shock and cold sensitivity - The Hindu
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