The neglected functions of intrinsically disordered proteins and the origin of life
Introduction
First crystallographic studies of proteins were made on stable proteins, which could be easily isolated and purified in sufficient quantities, and this may have resulted in an effect of bias as to the 3D-structure of proteins insofar that all the one studied were of a rather compact nature. For several decades this trend went on. Although the existence of short regions with higher flexibility was known at that time, the idea that the living cell harbours a large number of proteins exhibiting very extended regions with an unfolded conformation had to wait until about the onset of the new millennium (Wright and Dyson, 1999, Dunker et al., 2001, Uversky, 2002). This type of proteins are now generally known as ‘intrinsically disordered proteins’ (IDP's). IDP's and intrinsically disordered protein regions (IDPR's) are defined as functional proteins or protein regions that do not have unique 3D structures under functional conditions. Despite not being folded their functionality is encoded in an often quite conserved and specific amino-acid sequence with low overall hydrophobicity and high net charge and exhibiting distinctive conformational behaviour. IDP's can participate in one-to-many and many-to-one interactions giving rise to complex combinatorial situations (Uversky, 2013a, Uversky, 2013b, Uversky, 2015). Functions of IDP's are tuned via alternative splicing and posttranslational modifications (Uversky et al., 2008, Niklas et al., 2015). When getting out of control these proteins are often implicated in the pathogenesis of several diseases including cancer (Uversky, 2013a, Yakoucheva et al., 2002), cardiovascular diseases, amyloidoses, neurodegenerative diseases and diabetes (Uversky et al., 2008).
Section snippets
Kinds of IDP's and agreed functions
In the presently accepted view unfolded parts of IDP's are thought to exert the following general functions.
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In numerous complex proteins, which are particularly abundant in Eukaryotes, unfolded parts often link more globular regions. Interactions of these globular parts with one another and with other bio-molecules often necessitate large spatial flexibility, for which the conformational freedom of unfolded regions is very suitable. This flexibility allows many different conformational
Ignored functions are due to a wrong understanding of cell physiology
IDP(R)’s may have additional important general functions, which for historical reasons are ignored today. All these ignored functions have to do with the physical state of water and K+ in cytoplasm, both of which change when a cell or part of a cell changes from an inactive (resting) state into an active one or the reverse. The physico-chemistry of these changes are real phase transitions and unfolded protein (regions) are the actors. Insofar IDP(R)’s have decisive important functions in
What is wrong with membrane (pump) theory?
The rise of MPT goes back to an apparently decisive experiment of the famous physiologist Hill (1930). He measured the distribution coefficient of urea between resting muscles cells and the surrounding Ringer solution. It revealed a value close to one. So, the straightforward conclusion was that cellular water behaved similarly to the water outside. Hill also determined the osmotic pressure of these cells (Hill and Kupalov, 1930). He concluded that, since he demonstrated that cellular water is
What means ‘association’?
In 1973 Ling et al. (1973) repeated the crucial experiment of Hill (1930) and confirmed it. But they also largely extended this experiment by testing many additional solutes other than urea. So, they found that urea was the exception because of its small molecular size. Molecules with a larger size from 3 carbon atoms up to 12 gave distribution coefficients far below unity, roughly the lower the larger their size. The only conclusion was that cellular water cannot be ordinary water and must be
Physical approaches to the coherence of cells
Few years later another pioneer, Fröhlich, 1968, Fröhlich, 1975 independently introduced the idea of coherence in biologic systems. Applying electro-dynamical principles he theoretically derived that coherent behaviour might exist in living cells. Similar to Ling he also distinguished between static coherent behaviour, which was later called the ‘Fröhlich state’, and dynamic coherent behaviour named ‘Fröhlich waves’ (Fröhlich, 1983, Fröhlich, 1984, Fröhlich, 1986). His work allowed to predict
Ignored functions of IDP(R)’s
It is clear that MPT has lead to many misinterpretations still going on today. It was argued that AIH is a much better alternative paradigm for understanding cell physiology. Taking this paradigm seriously leads to several important but ignored functions of IDP's, which are specifically related to their unfolded structure. Since the most important aspects of AIH were treated on the pages before these ignored functions must only be briefly listed now.
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Each individual IDP(R) and all IDP(R)’s
The resonance recognition model of Cosic
As to the differences between individual IDP(R)’s Cosic presents a very interesting hypothesis called the ‘resonant recognition model’ (RRM) (Cosic et al., 1986, Cosic, 1990, Cosic, 1994). All proteins are in principle a linear sequence of amino acids. The RRM translates this linear information into a numerical series of electron-ion interaction potentials for each amino-acid residue and then transforms this series into the frequency domain using fast Fourrier transformation with the purpose to
The origin of solute distribution
Among the amino-acids, which are most easily obtained in Miller-type experiments and which also occur in the highest concentrations in some meteorites are Gly, Ala, Val, Asp, Glu and Pro. Also some organic acids are formed. The most abundant include formic acid, glycolic acid, propionic acid, lactic acid, acetic acid, succinic acid and several types of amino-butyric acids (deDuve, 1991). This list contains products which in actual metabolism take very central positions. De Duve argues that only
Conclusions
Mainstream biology followed a general physiological paradigm based on cellular water being normal water with K+ dissolved in it and whereby the cell membrane was thought to determine cytoplasmic concentrations of Na+, K+ and other permeable solutes. During the sixties on first sight this paradigm of MPT appeared very well established. After some years it became so evident that even its original name ‘membrane theory’ got out of use. Nevertheless Ling proved it to be wrong and developed a
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