Structural Biochemistry/Inherently Disordered Proteins
There are several entire and localized proteins that do not fold into 3-D structures yet are able to function fully. Instead of the usual linear pathway of proteins (sequence-to-structure
Structural Biochemistry/Inherently Disordered Proteins
There are several entire and localized proteins that do not fold into 3-D structures yet are able to function fully. Instead of the usual linear pathway of proteins (sequence-to-structure-to-function), these unfolded protein's functions come from different forms such as structured globules, collapsed disordered ensembles, and extended disordered ensembles). In addition, function can also arise from a disorder-to-structure transition. The understanding of these non 3-D structured proteins can help to diversify the knowledge of proteins and how they function in comparison to the globular 3-D structures.
Characteristics of Non-folding proteins
Since protein folding is directed by the amino acid sequence, the test to determine whether the non-folding proteins were guided by an amino acid sequence was carried out. The development of predictors to test out this hypothesis that the amino acid sequence specified no protein folding showed that the predictor accuracy was much better than expected by chance. This, in turn, revealed that protein non-folding is most likely within the amino acid sequence. The depletion of C, W, Y, F, I, V, and L residues, and the abundance of M, K, R, S, Q, P, and E residues reveals the decrease in residues that form hydrophobic interiors of structured proteins and the increase in residues that form the surface of structured proteins. This decrease and increase in the specific residues shows why the non-folding proteins do not fold into their 3-D structures.
Eukaryotes contain the biggest fraction of disordered proteins while archaea and eubacteria are in similar amounts, but far behind the amount present in eukaryotes. In addition, multicellular eukaryotes have more disordered proteins than mono-cellular eukaryotes.
Separating unstructured proteins into groups
The partitioning of structured proteins according to their amino acid sequence or function can be very useful because it allows for simple access to a wide variety of proteins and easy grouping of newly discovered ones. However, unstructured proteins and regions are hard to place into distinct groups because of their diversity, lack of a 3-D structure, and variance in their amino acid sequence. An example of this problem can be seen in the short amino acid linker in calmodulin, which forms a helix in the crystallized form but is flexible in solution. The disordered region in calmodulin allows for it to bind to a wide range of target sequence because the side-chains in the methionine-rich hydrophobic areas of the calcium-binding regions are flexible. Another example can be seen in the longer disordered region of PEVK in titin. PEVK can range from about 180 to 2174 residues, depending on the circumstances. The disordered region contains 180 residues in the cardiac muscle isoform while 2174 corresponds to the soleus muscle isoform. Both of these disordered regions help to maintain the appropriate length of muscle fibers. The wide range of function and variability in sequence portrays the difficulty in grouping these disordered proteins together.
Yet, partitioning was still accomplished through grouping the disordered proteins into homogeneous subsets. The disordered regions were randomly grouped into subsets and then different predictors were developed for each separate subset. The assembly of disordered regions were repartitioned into different groups again according to which predictor provided the best results. Then, new predictors would be constructed on the basis of the repartitioned subsets, and the steps would be repeated until there were no more changes with each of the new cycles. From this approach, three types or flavors were found and named V, C, and S. Flavor S contained a large amount of protein-binding regions, flavor V was rich in ribosomal proteins, and flavor C was high in the number of sites of protein modification.
Functions of disordered proteins and regions
Non-folding proteins and regions have significant duties in biological functions, taking part in signaling and regulatory pathways, through specific protein-protein, protein-nucleic acid, and protein-ligand interactions. Detailed functions of non-folding proteins and regions can be depicted in four categories: 1) molecular recognition, 2) molecular assembly, 3) protein modification, and 4) entropic chain activities. Non-folding proteins and their wide range of partners in interaction allow for the organization of complex protein-protein networks.
The disorder-associated and structure-associated functions in Swiss-Prot, a protein database, were identified recently. There were 310 structure-associated, 238 disorder-associated, and 170 structurally ambiguous, out of 710 functional keywords. This revealed the functional diversity of disordered proteins working in complement with structural proteins. Another test showed that the disordered proteins had more functions than the structural proteins, with the non-folding dealing with the signaling and regulatory processes while the folded proteins were associated with catalysis and transport.
Non-folding proteins and regions usually partook in molecular interactions controlled by localized binding sites such as eukaryotic linear motifs (ELMs), short linear motifs (SLiMs), and molecular recognition features (MoRFs). ELMs and SLiMs were bot