Tuesday, September 17, 2013

The Fate of Incorrectly Folded Proteins

Cellular proteins play many diverse and essential roles in the living cell.  The roles of these proteins range from providing structural integrity and function in muscle, as an example, to assisting in the many chemical reactions that are essential to ordinary metabolism.  They also play a fundamental role in maintaining homeostasis throughout the entire organism.  Each cell contains a rich population of diverse proteins numbering literally in the thousands.  Given this reality, it is essential that these proteins function normally.

Ribosomes are the organelles – the term literally means little organs -that function as the site for protein manufacture within the cell.  The blueprint for the structure of each unique protein is specified by the cell’s DNA.  Once the newly formed protein is complete, it is released from the ribosome and enters the cellular cytoplasm.  Upon release from the ribosomal surface, the nascent protein must fold into a precise configuration in order to attain full functionality.  This folding process is spontaneous.  However, the many diverse macromolecules that fill the cytoplasmic intracellular environment can impose a serious impediment to this folding process.
To meet this challenge, a sophisticated “chaperone” system is designed to reduce unfavorable interactions with the cytoplasmic environment in order to enhance the likelihood of successful folding.  It does this through a repetitious series of binding and release.  If these repeated attempts fail, evidence from scientific investigations has shown that the folding process is ultimately terminated for it may pose a threat to cellular energy resources and increase the abundance of toxic reactive oxygen species.

The nature of this termination mechanism – using growing yeast cells as the model organism – has been studied in detail by Dr. Chenchao Xu and his colleagues from the Temasek Life Sciences Laboratory at the National University of Singapore.  From their studies, they have shown that the folding process is terminated by a specialized pathway that utilizes the modification of the unfolded protein by an enzyme-mediated chemical reaction known as  o-mannosylation involving  the transfer of mannose – a sugar – to the serine – an amino acid – residue of the protein.   This modification was shown to disable folding entirely.
Finally, the authors of this study propose that the function of this mechanism designed to thwart repeated folding attempts is to end apparently futile chaperone-directed folding.  As mentioned previously, repeated and unsuccessful cycles of folding can seriously impinge upon cellular energy reserves.  The fate of unfolded proteins is their ultimate degradation.

This kind of study helps to elucidate complex cellular mechanisms and highlights the importance of maintaining homeostasis within the cellular environment.

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