Protein Folding Malfunction and Disease

A HUM-MOLGEN article entitled 'Protein Folding Lost In Translation' reveals a link between diseases and an accumulation if misfolded proteins. The specific cause of the accumulation is attributed to a malfunction of the translation process which is essential for protein synthesis. The article cited a study of mice and what is referred to as a "sticky mutation." Susan Ackerman and colleagues were involved in the study. The italicized article follows along with my comments in bold print.


A new mechanism that could underlie certain neurodegenerative diseases is published online this week by Nature. The researchers reveal that upsetting the accuracy of translation, the process by which messenger RNAs are coded into proteins, can lead to the accumulation of misfolded proteins.

The reason that accumulated, misfolded proteins become problematic as a result of translation function impairment, lies in the fact that all coded for proteins, containing the amino acid alanine, would be affected by this malfunction. Although amino acid substitution can occur without negating function, the number of substitutions, likely to occur as a result of this type of mutation, indicates that protein malfunction would overwhelm the capacity of coping cellular mechanisms.


Susan Ackerman and colleagues studied mice with the so-called 'sticky' mutation, which develop tremors, movement problems and cellular death of cerebellar neurons. The results of the study implicate the faulty manufacture of transfer RNAs (tRNAs) - the molecules that insert amino acids into their appropriate position during translation - as the reason behind the neurodegeneration seen in sticky mice. The team showed that the sticky mutation disrupts an enzyme called alanyl-tRNA synthetase, which attaches a specific amino acid to tRNA molecules. The mutation causes the production of proteins containing aberrant amino acids, and these proteins cannot fold correctly and so accumulate within neurons, killing them. The researchers propose that some heritable diseases could be caused by mild mutations that disrupt tRNA synthetase enzymes.

Proteins that do not fold correctly lose their functional capabilities. They can then impair other cellular functions. However, cells have mechanisms that identify and degrade such proteins. There is a biochemical concept known as protein turnover. The following alludes to this process.

In healthy adults, the total amount of protein in the body remains constant, because the rate of protein synthesis is just sufficient to replace the protein that is degraded. This process, called protein turnover, leads to the hydrolysis and resynthesis of 300 to 400 g of body protein each day. The rate of protein turnover varies widely for individual proteins. Short-lived proteins (for example many regulatory proteins and misfolded proteins) are rapidly degraded, having half-lives measured in minutes or hours. Long lived proteins, with half-lives of days to weeks, constitute the majority of proteins in the cell. Structural proteins, such as collagen, are metabolically stable, and have half-lives measured in months or years.1

Protein malfunction is natural as are cellular mechanisms to cope with the problem. The article refers to a condition wherein the amount of impaired proteins can accumulate to the point of overwhelming the coping mechanisms. The article and larger issues which encompass it are interesting from the perspective of life's origins and history. Loss of protein function is inevitable. Sometimes it occurs at the outset of the protein synthesis process as indicated in this post. Other times it occurs subsequently as indicated in the quoted reference. In any case misfolded and other malfunctional proteins can become obstacles to the functions needed to sustain life.

Mechanisms that identify and degrade proteins are clearly essential. Essential functions are red flags in objective assessments of the adaquacy of natural history paradigms. Setting aside the matter of how protein synthesis mechanisms come about and how their functionality is acquired, data indicates that some means of coping with malfunctional proteins is required at an early point in theoretical musings about how life came about and subsequently evolved. The implications of this specific issue will be further analysed in future posts about proteins.


References:

1. 'Biochemistry'; Page 244; Pamela C. Champe, Richard A. Harvey and Denise R. Ferrier; Lippencott, Williams & Wilkens; 2005.