Science & Technology

Overview - The traditional concept that a well-defined three-dimensional structure of a protein is one of the main requirements for its function can be found in many high-school textbooks. Recent evidence, however, has shown that the lack of a stable conformation may in some cases provide functional advantages by allowing a protein to more easily adapt to different cellular stimuli. Flexible linkers in complex multi-domain proteins as well as specific protein regions that can adopt different conformations upon binding to different partners, or in particular cell compartments, provide additional examples of the biological importance of flexible, adaptable states. Therefore, while the functional importance of structural scaffolds is still well recognized, as witnessed by the steady growth in the number of the three-dimensional structures deposited in the Protein Data Bank (PDB), the highly dynamic and flexible nature of these IDPs and IDRs is now being recognized as an important feature for protein function in vivo. Current estimates suggest that as many as 25-40% of the proteins in eukaryotes are IDPs or contain IDRs. Several individual IDPs have been shown to be associated with human pathologies (cardiovascular diseases, amyloidoses, type II diabetes); the uncontrolled transition to disordered states or the aggregation of disordered protein modules leads to disease (neurodegenerative diseases such as Alzheimer’s, Parkinson’s and prion diseases). More recently, IDRs have also been described as a general mechanism through which cell components escape to regulatory mechanisms and may be related to the development of cancer. These findings raise questions regarding the importance of IDPs and IDRs in processes at the basis of life and disease. The relationship between intrinsic disorder and protein function, however, is still largely unclear and more investigation is required to better understand the biological role of structural disorder.

NMR spectroscopy provides a unique tool to access information at atomic resolution in different aggregation states as well as in the native-like environment of proteins in living cells. It is particularly suited to study heterogeneous and flexible macromolecules. However a strong integration of NMR with complementary techniques (other spectroscopic techniques, computational approaches, biochemistry, molecular biology, cell biology) is necessary to address complex systems and provide answers to biochemically and medically relevant problems.

The training program proposed here is crucial for rising a new generation of young scientists for the biomedical and pharmaceutical industries who are aware of the basic change in awareness concerning the classical structure-function relationship of proteins. This novel concept is currently not covered in mainstream textbooks on biochemistry and molecular biology, nor in standard college courses; thus, students are primarily taught the traditional concepts. Since many important proteins involved in human medical conditions or present in pathogenic microorganisms have a high level of intrinsic disorder, they cannot be fully understood unless we take account of the structural disorder. Recent results show that in many cases, novel drug candidates can be developed against binding partners of IDPs or IDPs themselves. These endeavours will require scientists trained in this novel discipline.