Structural Biochemistry, Membrane Proteins, Folding

Membrane Protein Folding

The study of membrane protein folding has been complicated by several factors. Historically, membrane proteins have been very difficult to crystallize due to their large amounts of hydrophobic residues. Proteins that reside in these biological membranes have different surface properties than water-soluble proteins. The proteins are more so affected by the lateral forces and elastic forces from being within the membrane. Duplicating these conditions in order to observe a membrane protein in vitro has been difficult due to the fact that once the membrane protein has been separated, it either unfolds or no longer stays functional.

Manipulating Lipid Bilayer

Maniuplating the lipid bilayer to observe proteins has been increasingly successful. Studies used on smaller water-soluble proteins are very effective with this method. The combination of kinetic and thermodynamic studies of the small water-soluble proteins have been feasible to observe the helical proteins which contain a lot of alpha helices.

Consequences of incorrect protein folding

Incorrectly folded proteins are associated with prion-related illnesses such as Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), amyloid-related illnesses such as Alzheimer's disease and familial amyloid cardiomyopathy or polyneuropathy, as well as intracytoplasmic aggregation diseases such as Huntington's and Parkinson's disease. These age onset degenerative diseases are associated with the aggregation of misfolded proteins into insoluble, extracellular aggregates and/or intracellular inclusions including cross-beta sheet amyloid fibrils. While it is not completely clear whether the aggregates are the cause or merely a reflection of the loss of protein homeostasis, the balance between synthesis, folding, aggregation and protein turnover, the recent European Medicines Agency approval of Tafamidis or Vyndaqel (a kinetic stabilizer of tetrameric transthyretin) for the treatment of the transthyretin amyloid diseases suggests that it is the process of amyloid fibril formation and not the fibrils themselves that causes the degeneration of post-mitotic tissue in human amyloid diseases.[18] Misfolding and excessive degradation instead of folding and function leads to a number of proteopathy diseases such as antitrypsin-associated emphysema, cystic fibrosis and the lysosomal storage diseases, where loss of function is the origin of the disorder. While protein replacement therapy has historically been used to correct the latter disorders, an emerging approach is to use pharmaceutical chaperones to fold mutated proteins to render them functional.

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