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Decades ago, Christian Anfinsen won the Nobel Prize for demonstrating that all of the information required for a protein to assume its native 3D structure is contained within the amino acid sequence of the polypeptide chain. More recently, it has become clear that numerous devastating human diseases are caused when proteins fail to fold correctly, either due to a genetic mutation, or environmental damage. Yet despite intense effort, we still do not understand many of the principles governing protein folding (the connection between sequence and 3D structure), nor exactly what happens when protein folding fails, and why.

Since Anfinsen's seminal experiments, the vast majority of protein folding research has focused on understanding how an unfolded, full length polypeptide chain can quickly and efficiently fold to form its native structure in a test tube, in a dilute purified solution. Yet in cells, proteins do not appear all at once upon dilution out of denaturant. Instead, they are synthesized vectorially from N- to C-terminus by the ribosome, and a large fraction of these chains are subsequently transported vectorially across one or more membranes to reach another compartment of the cell, or the extracellular milieu. The vectorial appearance of the polypeptide chain can have a profound effect on the mechanism for protein folding, affecting the kinetics of the folding process and whether a given protein will fold correctly to its native structure, or aggregate. Below are some articles from our lab that explore these topics in more detail:

Braselmann E, Chaney JL & Clark PL (2013) Folding the proteome. Trends in Biochemical Sciences 38, 858-861. [PDF] [cover]

Clark P.L. (2004) Protein folding in the cell: Reshaping the folding funnel. Trends in Biochemical Sciences 29: 527-534. [PDF] [cover]

Evans M.S., Clarke T.F. & Clark P.L. (2005) Conformations of co-translational folding intermediates. Protein & Peptide Letters 12: 189-195. [PDF]