p284

Proteins with definite equilibriums structures are not majority

We are taught in biochemistry and physics that proteins are folded into their equilibrium structures under their natural conditions. However, if one starts to question how strong experimental/empirical evidence there is for the statement above, one must conclude that the evidence is not strong.  First of all, it is true that there are many proteins that fold into definite structures, but there are not many experiments that demonstrated that these structures are indeed in equilibrium (the minimum free energy structures). It is often said molecular dynamics demonstrates the stability of the structures obtained by e.g., crystal structure analysis, but what is demonstrated is only the metastability of these structures (local stabilities only). We even have:

Folding location overrides binding preference

Tottey et al., “Protein-folding location can regulate manganese-binding versus copper- or zinc-binding,” Nature  455 , 1138 (2008). 

The paper studies the most abundant Cu$^{2+}$-protein, CucA (Cu21-cupin A), and the most abundant Mn21-protein, MncA (Mn21-cupin A), in the periplasm of the cyanobacterium  Synechocystis PCC 6803.

No folded state may be needed for enzymatic activities

Bemporad Biological function in a non-native partially folded state of a protein

EMBO J  27 1525 (2008)

*Biological activity of conformational states distinct from fully folded structures could be more common than previously thought. 

*Non-native state populated transiently during folding of the acylphosphatase from  Sulfolobus solfataricus is enzymatically active.

 An interesting recent topic is the disordered proteins. Majority of proteins have at least their some portion unstructured (without definite equilibrium structures), and they have quite important roles in the cell:

Sponer et al.,

Tight Regulation of Unstructured Proteins: From Transcript Synthesis to Protein Degradation

Science  322 1365 (2008)

(BG) Altered abundance of several intrinsically unstructured proteins (IUPs) has been associated with perturbed cellular signaling that may lead to pathological conditions such as cancer.

*Abundant phosphorylation and low stochasticity in transcription and translation indicate that the availability of IUPs can be finely tuned. Fidelity in signaling may require that most IUPs be available in appropriate amounts and not present longer than needed.

According to this paper, among 6702 proteins in yeast only 1971 are folded into definite structures.2711 proteins have about 70-90% definite structures, and the remaining 2020 are highly unstructured proteins. As can be seen in the about quotation, since unstructured proteins are more rigorously regulated than the structured ones, the former are expected to have important functions. Indeed, it is expected that they are deeply involved in e.g., signal transduction [Dunker,Function and structure of inherently disordered proteins, Curr Op Sys Biol  18 , 756 (2008)]. Many signal proteins with definite structures are know to bind to disordered proteins. The interactions among disordered potions of proteins are regarded as a cause of dosage imbalance that could happen after gene duplications.

 It is know that the portion of disordered proteins increase in higher eukaryotes.

 The author of this book believes the name `unstructured protein’ is more appropriate than `disordered protein.’