New study suggests cellular metabolites are bona fide members of proteostasis as they assist in protein folding irrespective of the molecular chaperones.
AUG 24, 2020 | BY RATNESHWAR THAKUR
Our body is around 16 percent proteins that perform nearly every biological process necessary for life. For this, Proteins need to fold into a particular conformation to perform the functions like maintaining cell shapes, catalysing enzymatic reactions, cellular communications and much more. Hence, better understanding of protein folding and strategies that a cell employs to maintain a healthy proteome can help us to understand protein-folding related diseases like Alzheimer’s disease, Parkinson’s disease, Type-2 diabetes, and many more!
The cellular machinery that ensures healthy proteins is called the proteostasis (protein homeostasis) machinery. While the concept of proteostasis has been studied for ages, scientists have mainly known about molecular chaperones mediated protein folding and degradation, but protein folding and their homeostasis -- still holds many mysteries.
Now a research team led by Dr. Kausik Chakraborty at CSIR-Institute of Genomics and Integrative Biology in collaboration with CSIR-National Chemical Laboratory (Pune) - unravel that cellular metabolites are bona fide members of proteostasis as they assist in protein folding irrespective of the molecular chaperones.
Metabolites are the small molecules that are end products and intermediates of cellular metabolism. Many metabolites are also used as biomarker for diagnosis like measurement of glucose in cerebrospinal fluid (CSF) to diagnose the suspicion of infection and inflammation etc.
This is the first report where Chakraborty’s team shows that the proteostasis capacity of a cell depends on cellular concentration of some of these metabolites. They say changes in the metabolic state can program a cell to handle proteotoxic stress related to protein folding. The results of this study were published in the journal “Nature communications.”
Metabolites modify the thermodynamics of protein folding using the redundant elements present in proteins (such as amino acids) and nucleic acids (such as introns and repetitive DNA) to buffer the effect of point mutations in their conformation critical for functions.
In this study, Chakraborty’s team used the capability of E. coli strains differing in their endogenous metabolite pool to buffer the same set of mutations on model proteins differently. Dr. Kanika Saxena narrowed down to two E. coli strains that were genetically different only in their metabolite pool to address the question. They used comprehensive library of mutants of two model proteins GFP (Green Fluorescent Protein) and GmR (Gentamicin-acetyl transferase) to study the protein folding capacity of bacterial cells. Use of high throughput techniques like Flow cytometry (for GFP-increase in fluorescence) and NGS based deep sequencing (for GmR- increase in mutant read count) were used to quantify cellular mutational buffering capacity.
“This study suggests these evolved organisms can fix the metabolic changes into their DNA required to fold the proteins better,” added Dr. Manish Rai, one of the author in this study.
Chakraborty’s team think of metabolites as ‘front line warriors’ of proteostasis machinery that are no less important than the fancy chaperone proteins. When a cell faces any problem with protein folding, be it due to change in its environment, niche, or pathophysiological state, it can change its metabolism very quickly to keep the cell alive long enough for chaperones to jump in and save the day. This is further endorsed by alteration in metabolism being the preferred route for an organism to evolve to a particular stress, for example, high temperature or high salt.
The research team included Kanika Verma, Kanika Saxena, Rajashekar Donaka, Aseem Chaphalkar, Manish Kumar Rai, Anurag Shukla, Zainab Zaidi, Rohan Dandage, Dhanasekaran Shanmugam and Kausik Chakraborty. The study was funded by CSIR, DST and Welcome Trust-DBT India Alliance.
Journal Reference:
Distinct metabolic states of a cell guide alternate fates of mutational buffering through altered proteostasis
