Crossroad Intermediates as ‘Folding Pathway’ Control Mechanism of Gene Expression

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CrossroadIntermediates (CRI) are those folding pathway intermediates that are situated at crossroads between protein folding and aggregation. CRI can either lead to folding of protein into native functional state (if one pathway is followed) or lead to formation of aggregated non-functional state (if another pathway is followed). We propose here for the first time, that formation of CRI may be the last control mechanism of gene expression chosen by Nature (after transcriptional, post- transcriptional, translational control mechanisms) - an event that occurs just before formation of native state in order to maintain concentration of particular protein. Since this step occurs during folding of protein, we name it as ‘Folding Pathway’ Control Mechanism of gene expression. We also propose that switch mechanism, for these CRI following a particular pathway lies in the concentration of that protein. Notion that Protein Folding pathway should also be subjected to control mechanism has long been ignored in the history of biological sciences. Information in this article will help to reshape and strengthen our understanding of Control of Gene Expression.

Gene Expression is set of steps that starting from gene ultimately leads to production of proteins or functional RNA product. (In this communication, we are concerned with protein synthesis; hence in all further description gene expression would mean production of proteins from genes). It is the most important function of cell to maintain its structure and function. Gene Expression starts with Transcription (production of RNA from DNA) and then leads to Translation (production of proteins from RNA). When RNA is synthesized from DNA by process of transcription that occurs in nucleus of cell, it undergoes several modifications known as Post- Transcriptional Modifications and then transported out of nucleus. In cytoplasm, RNA is translated into protein sequence. Protein then undergoes Post-translational modifications (in some cases). Linear chain of amino-acids is then folded into 3-dimensional structure by process of Protein Folding before it becomes functionally active. Transcription, Post-Transcriptional Modifications, Translation, Post-translational modifications- all constitute the elaborate process of Gene Expression.

As much as Gene Expression is important, so is its control, in order to maintain timing and concentration of protein at a particular site in cell. Although same DNA sequence is present in all cells, it is control of gene expression that defines protein content (and subsequently content of other bio molecules) of a particular cell at a particular time and makes the cell specialized and distinct from other cells. Control of gene expression is exercised at each step involved in this process. Transcriptional control forms the first step of control and is usually the most important step. Post-transcriptional control occurs after mRNA is synthesized. Once protein is being synthesized from mRNA, translational control mechanism takes over and tries to maintain concentration of protein being synthesized. The protein can also be subjected to activity control mechanism switching it between active or inactive states.

After being synthesized by translation, native linear chain of polypeptide has to fold in order to achieve its functional state by the process known as Protein Folding. Protein folding is thus described as a process by which a disordered protein chain diffuses across a high-dimensional energy landscape and finally reaches the folded ensemble. It has been inferred that proteins must fold to their unique native state through multiple unpredictable routes and intermediate conformations. The search problem involved in folding however has been simplified through the evolution of folding energy landscapes that are funnelled. Funnel-shaped energy landscape pictures that proteins must fold energetically downhill along with decrease in entropy in order to form native conformation. The free energy landscape can provide a quantitative description of folding dynamics, if determined as a function of an optimally chosen reaction coordinate. Single molecule studies have provided novel insights about how the dynamic sampling of the free energy landscape dictates all aspects of protein behaviour; from its folding to function.