P Tompa

..As intrinsic protein disorder has been linked with complex responses to environmental stimuli and communication between cells, an additional possibility is that structural disorder may effectively increase the complexity of species...

..The recent high-throughput analyses of protein-protein interactions and protein complexes in the cell generated data that enable to address this issue by bioinformatic means...

..Using these details, we chart out how far the field has progressed only to emphasize the long road ahead before chaperone function can be firmly established as part of the physiological mechanistic arsenal of the emerging group of IDPs...

..Given the crucial role of protein disorder in protein-protein interactions and in regulatory processes, we envision that fuzziness will become integral to understanding the interactome...

..Owing to the apparent functional benefits, we expect to see many more examples of this parsimonious use of protein material in complex metabolic networks...

..e. disorder in the bound state that may serve different functions, such as the accommodation of destabilizing residues and the mediation of secondary interactions between protofibrils...

..Via all these details, it is demonstrated that in only a couple of years after its conception, the idea of protein disorder has already come of age and transformed our basic concepts of protein structure and function...

..7% and 15%, respectively. In keeping with these and other details, a novel "entropy transfer" model is presented to account for the mechanistic role of structural disorder in chaperone function...

..With these points, we argue that these long disordered regions should be recognized as a distinct class of biologically functional protein domains...

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..We interpret this finding by the direct functional involvement of disorder, which distinguishes it from secondary structural elements and endows it with tertiary structural attributes...

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..Thus, protein disorder is a widespread and functionally important phenomenon, which needs to be characterized in full detail for understanding complex organisms at the molecular level...

..In this review, recent findings are surveyed to illustrate that this novel but rapidly advancing field has reached a point where these proteins can be comprehensively classified on the basis of structure and function...

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..Furthermore, these activators open new avenues to cell biological studies of calpain function and eventually may alleviate pathological states caused by calpain malfunction...

..Our results show that calpain is sensitive to the frequency of fast Ca2+ oscillations in vitro, which is of potential physiological significance...

..These results suggest that domain III might be the primary lipid binding site of calpain and may play a decisive role in orchestrating Ca2+- and lipid activation of the enzyme...

..A schematic model of this "extended transducer" mechanism is presented...

..Our work is the first experimental evidence that DUK114, and possibly other members of this family, are molecular chaperones...

..These results establish a connection between LMs and molecular recognition elements of intrinsically unstructured proteins (IUPs), which realize a non-conventional mode of partner binding mostly in regulatory functions...

..Moreover, we analysed Calpain C RNA expression during Drosophila development by RT-PCR and RNA in situ hybridization, which revealed strong expression in the salivary glands...

..6 +/- 0.3 J g(-1) K(-1). Thus, in a thermodynamic sense, crystalline protein and its hydrate layer behave as a highly-interconnected single phase...

..e. they use their binding energy for folding. Overall, our findings provide a structural rationale to the prior suggestions that many IUPs are specialized for functions realized by protein-protein interactions...

..In support of this conclusion, we show that IDPs that bind chaperones also tend to bind other proteins...

..Finally, we wrap up the chapter with the results on two proteins (a globular and an intrinsically disordered)...

..These differences disappear in the amyloid state, suggesting basically the same surface topology, irrespective of the initial monomeric state...

..We suggest that these in vitro observations are relevant in vivo and the calpain cascade may play an important role in coordinating the functioning of calpains in living cells...

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..The kinetic parameters of these mutant enzymes support a model featuring shrinkage of transducer as a contributor to structural changes involved in calpain activation...

..Protein disorder, nevertheless, plays a key signalling role in many cases...

..g. EWS-ATF). Our findings also suggest novel strategies of intervention against the ensuing neoplastic transformations...

..To emphasize the possible importance of this structural trait, we propose that these motifs be called primary contact sites in IUPs...

..All these features expand the capacities of ordered complexes and give rise to efficient regulatory mechanisms...

..These observations highlight possible novel aspects of the promiscuous functions of ribosomal proteins outside of the ribosome...

..The hypothesis is advanced that these distinct distributions of calpain subunits may be related to the transport of these enzymes in nerve cells...

..Equipped with all this information, we may now embark on the genetic modification of family members, interpreting mutant phenotypes in terms of the cell biology of calpains...

..Optional to the prediction are built-in parameter sets optimized for predicting short or long disordered regions and structured domains...

..Overall, our analysis suggests that calpain regulates the cell cycle at more points than previously thought...

..The expression of this protein in vivo, as assessed from its appearance in expressed sequence tag clones, is rather limited, making it an example of a tissue-specific, rather than ubiquitous, small subunit...

..e., these IDPs do remain in a state of rapidly interconverting structural ensemble. Altogether, our results underline that structural disorder is the physiological state of these proteins...

..This scenario may explain why, in a structural sense, the prion protein is still en route toward becoming a foldable globular protein...

..In the case of micro- and m-calpain, this substrate is kinetically superior to commercially available ones, and it can be used for the in vivo assessment of the activity of these ubiquitous mammalian calpains...

..In S2 cells, calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes...

..Our results affirm that in contrast with globular proteins IDPs are resistant to cold treatment. The theoretical and functional aspects of this observation are discussed...

..By discussing several examples, we demonstrate that dual coding may be an effective mechanism for the evolutionary appearance of novel intrinsically disordered regions with new functions...

..Phosphorylation of this site also affects proteolytic sensitivity of MAP2c, which might represent a further level of control in this system. Thus, the phosphorylation state of T(220) may be a primary determinant of microtubule function...

..The theoretical treatment and experimental approach presented in this article may have general utility in characterizing proteins that belong to this novel structural class...

..Advantages and drawbacks of the various approaches are outlined in anticipation of future inventions in the field that will hopefully elevate IUP research to the truly proteomic level...

..Finally, we also would like to point out the utility of our 2DE/MS technique for discoveringor, as a matter of fact, rediscoveringIDPs even from the complicated proteome of an advanced eukaryote...

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..It is suggested that a new model describing the structure-function relationship of IDPs has to encompass such structural and functional promiscuity inherent in the disordered state of IDPs...

..Overall the reproducibility and ease of performance of this technique may promote the proteomic scale recognition and characterization of protein disorder...

..Therefore, the categoric classification of 'ubiquitous' vs. 'tissue-specific' calpains is a simplification...

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..002 for Immediate and p=0.014 for Delayed Logical Memory), but not in males (p=0.31 and 0.83, respectively). We conclude that functional variation of the androgen receptor gene is able to modulate memory function in women...

..This finding implies that IUPs draw a functional advantage from preformed structural elements, as they enable their facile, kinetically and energetically less demanding, interaction with their physiological partner...

..The primary focus of our review is the interpretation of prediction results in a way that enables segmentation of proteins to separate ordered domains from disordered regions...

..An emphasis is also given to a somewhat different approach, in which ordered/disordered regions are explicitly delineated to the end of making constructs amenable for structure determination even when disordered regions are present...

..We suggest that these findings provide the rationale for the mechanism of how these proteins avert the adverse effects of dehydration stresses...

..We present a model including these features largely ignored so far and show that it adheres satisfactorily to the observed phenomenology of prion replication...

..These results, in combination with bioinformatic and biochemical data on the securin/separase interaction, shed light on the inhibitory action of securin on separase...

..Taken together, these observations point to significant binding-induced local folding transitions in calpastatin, in a way that ensures highly specific, yet reversible, action of the inhibitor...

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