Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go?
The structure-function paradigm claims that a specific function of a protein is determined by its unique and rigid three-dimensional (3D) structure. Thus, following its biosynthesis on the ribosome, a protein must fold to be functional. This idea represents one of the cornerstones of modern biology. Numerous cases when, due to the effect of environmental factors or because of genetic defects (mutations), a polypeptide chain has lost its capability to gain a proper functional 3D structure (i.e. became misfolded), seem to confirm this concept. Consequences of such misfolding are well known and represent lost of function, aggregation, development of conformational disorders and cell death. However, the recent revelation of countless examples of intrinsically disordered proteins has cast doubt on the general validity of the structure-function paradigm and revealed an intriguing route of functional disorder. Thus, in a living cell, a polypeptide chain chooses between three potential fates - functional folding, potentially deadly misfolding and mysterious nonfolding. This choice is dictated by the peculiarities of amino acid sequence and/or by the pressure of environmental factors. The aim of the present review is to outline some interesting features of these three routes.
Uversky
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Institute for Biological Instrumentation, Russian Academy of Sciences, 142292 Pushchino, Moscow Region, Russia. uversky@hydrogen.ucsc.edu
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D051843:Synucleins; D013816:Thermodynamics
D000682:Amyloid; D009419:Nerve Tissue Proteins; D051843:Synucleins