The Science of Existence (76-2) Protein Folding

Protein Folding

Over time, Nature improved protein folding so that more complex structures were able to develop. ~ German molecular biomechanist Frauke Gräter

Proteins are produced in a linear sequence. The last step in protein production is an elaborate folding to a shape that is energetically in repose.

Chaperonin are proteins that provide scaffolding for the first folding of new proteins. In a high-speed origami, a protein assumes its final resting structure in a series of rapid incremental steps. This process takes only a few seconds, thanks to active guidance by chaperonin.

A protein partly unfolds to work. How a protein folds/unfolds, and at what speed, has much to do with its performance. The intricate 3d conformation of a protein is essential to proper functioning.

A major force behind protein folding and polypeptide interaction is the avoidance of water by hydrophobic amino acids. Internal friction, which reflects the energy landscape of the protein, plays an important role in the dynamics of folding, and the ability of a protein to function properly. The folding process of a protein is regulated by a formidable network of other proteins, and other, smaller molecules.

There is a sea of small molecules – ligands – with which proteins live in a cell. These ligands, which are very small molecules only about 100 daltons in size, are critical in determining the behavior of folding macromolecules on the order of 100 kilodaltons in size, that is 1,000 times larger. It’s like the mouse telling the elephant what to do. ~ American biochemists Lila Gierasch & Scott Garman

Many proteins have varying degrees of folding. 30% of human proteins have unfolded portions.

Whether a portion of a protein is folded or not, or even appears disordered, is scant indication of what it may do. A protein operates orchestrally; all portions have some part to play. The odd bits may be the piece that give a protein its versatility.

Many diseases result from misfolded proteins (prions), notably neurodegenerative diseases associated with aging, such as Parkinson’s, Huntington’s, and Alzheimer’s. Prions refold from a harmless form into one that is malicious and contagious, initiating a chain reaction that creates a prion aggregation.

RfaH is a protein which activates genes that allow E. coli bacteria to launch a successful attack on a host, inciting disease. It does so by folding itself into different shapes, and by doing so is able to perform vastly different tasks. Specifically, RfaH can fiddle with both genetic transcription and translation – coupling the two together – by smartly changing its shape.

Dihydrofolate reductase (DHFR) is an enzyme common to E. coli bacteria and humans and everything in between. DHFR structure is almost identical throughout all life forms; conserved through evolution, as its function is critical for the synthesis of DNA. But how DHFR unfolds to expose amino acids differs between bacteria and primates. This distinction in atomic dynamics makes a significant difference.

DHFR motion evolved to fit the cellular environment. Human DHFR is so well-tuned for its own cells that it won’t work in bacteria: the product molecules in E. coli are packed too tight for human DHFR to function.