Intrinsically Disordered Proteins and their Implications in Disease

By Aarushi Bellani

Proteins are considered to be the building blocks of all life and the process of their formation is strictly regulated, resulting in a very specific 3D structure unique to each protein. A new subset of proteins has been found that is characterised by the lack of rigid structures either entirely or in some localized regions of their sequence. These are known as intrinsically disordered proteins (IDPs) and play important roles in many cellular processes such as signaling, cell cycle regulation, and transcriptional regulation (Uversky and Dunker, 2010). 

Generally, protein function is determined largely by the way the protein is folded and the resulting secondary or tertiary structure, however, the discovery of IDPs has refuted this and has shown that the flexibility of certain proteins is what gives them the ability to perform their unique functions. The ‘intrinsic disorder’ that is being referred to here is the fact that unlike most proteins, IDPs don’t have an equilibrium position and have highly variable Ramachandran angles and atomic positions (Uversky et al., 2008). Due to their importance in cellular architecture, they have been implicated in a multitude of diseases such as various types of cancer, neurodegenerative disorders as well as diabetes (Uversky et al., 2008). 

One of the main diseases that IDPs are known to play an important role in is cancer. The main determinant of survival in almost all cancer types is the process of metastasis that is caused by epithelial-mesenchymal transition due to phenotypic plasticity. It was long believed that this was primarily a result of mutations in the genome, however, a large portion of evidence points to a significant contribution of IDPs (Mooney et al., 2016). Since these proteins lack a definitive structure, they adopt multiple conformations that lead to promiscuous interactions generating a new form of disturbance called conformational noise, which similar to transcriptional noise, leads to heterogeneity (Mahmoudabadi et al., 2013). This conformational noise specifically creates a variety of protein network configurations, which the cancer cell can sort through to find the most suitable configuration for maximum plasticity. Since a lot of these proteins are also transcriptional factors, their flexibility leads to transcriptional noise as well making cancer cells highly malleable (Jia et al., 2017). 

Due to their extreme impact on cancer prognosis, IDPs are being considered as potential drug targets in various cancer types. A hallmark of almost all cancers is the suppression or loss of expression of the tumour suppressor gene p53. This protein is also intrinsically disordered at its N-terminus (Well et al., 2008) and is seen in both ordered and disordered confirmations in solution (Lowry et al., 2008). A majority of drugs function by blocking protein-protein interactions and in cancer the protein that p53 binds to is Mdm2 (Mouse double minute 2 homolog), which negatively regulates p53 expression (Momand et al., 1992). Since the binding site of p53 is intrinsically disordered, the interaction between it and another protein is not as stable as that between two structurally ordered proteins and can thus be effective targets (Wang et al., 2011). 

Although owing to phenotypic plasticity IDPs are heavily involved in cancer, they have multiple other properties that make them targets in other diseases such as Alzheimer’s disease and Parkinson’s disease. Amyloid-β, α-synuclein and Tau are the three main IDPs associated with Alzheimer’s and Parkinson’s disease and are being extensively looked at as potential drug targets. In Alzheimer’s disease, the formation of senile plaques and neurofibrillary tangles (due to Tau accumulation) is known to be one of the leading causes of pathology. Drugs are thus being purposed to target the dynamic nature of these molecules and disrupt disease causing pathways (Ambadipudi and Zweckstetter, 2016). For example, the tricyclic phenothiazine methylene blue has been found to prevent Tau aggregation by specific reduction and oxidation of Tau’s two native cysteine residues causing it to stay in its monomeric state and preventing interaction with other Tau molecules (Akoury et al., 2013). 

With the fundamental knowledge of protein structure and function being disrupted by the emergence of IDPs, it is evident that they will have a significant impact on drug discovery pertaining to many diseases and will hopefully provide opportunities to develop highly effective treatments for some very devastating ailments.   

References:

Akoury, E., Pickhardt, M., Gajda, M., Biernat, J., Mandelkow, E. & Zweckstetter, M. (2013) Mechanistic basis of phenothiazine‐driven inhibition of Tau aggregation. Angewandte Chemie International Edition. 52 (12), 3511-3515.

Ambadipudi, S. & Zweckstetter, M. (2016) Targeting intrinsically disordered proteins in rational drug discovery. Null. 11 (1), 65-77. Available from: doi: 10.1517/17460441.2016.1107041.

Jia, D., Jolly, M. K., Kulkarni, P. & Levine, H. (2017) Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory. Cancers. 9 (7), 70. Available from: doi: 10.3390/cancers9070070.

Lowry, D. F., Stancik, A., Shrestha, R. M. & Daughdrill, G. W. (2008) Modeling the accessible conformations of the intrinsically unstructured transactivation domain of p53. Proteins: Structure, Function, and Bioinformatics. 71 (2), 587-598. Available from: doi: 10.1002/prot.21721.

Mahmoudabadi, G., Rajagopalan, K., Getzenberg, R. H., Hannenhalli, S., Rangarajan, G. & Kulkarni, P. (2013) Intrinsically disordered proteins and conformational noise: implications in cancer. Cell Cycle (Georgetown, Tex.). 12 (1), 26-31. Available from: doi: 10.4161/cc.23178.

Momand, J., Zambetti, G. P., Olson, D. C., George, D. & Levine, A. J. (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 69 (7), 1237-1245. Available from: doi: 0092-8674(92)90644-R

Mooney, S. M., Jolly, M. K., Levine, H. & Kulkarni, P. (2016) Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins. Asian Journal of Andrology. 18 (5), 704-710. Available from: doi: 10.4103/1008-682X.183570.

Uversky, V. N. & Dunker, A. K. (2010) Understanding protein non-folding. Biochimica Et Biophysica Acta. 1804 (6), 1231-1264. Available from: doi: 10.1016/j.bbapap.2010.01.017.

Uversky, V. N., Oldfield, C. J. & Dunker, A. K. (2008) Intrinsically Disordered Proteins in Human Diseases: Introducing the D2 Concept. Annual Review of Biophysics. 37 (1), 215-246. Available from: doi: 10.1146/annurev.biophys.37.032807.125924.

Wang, J., Cao, Z., Zhao, L. & Li, S. (2011) Novel strategies for drug discovery based on intrinsically disordered proteins (IDPs). International Journal of Molecular Sciences. 12 (5), 3205-3219.

Wells, M., Tidow, H., Rutherford, T. J., Markwick, P., Jensen, M. R., Mylonas, E., Svergun, D. I., Blackledge, M. & Fersht, A. R. (2008) Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain. Proc Natl Acad Sci USA. 105 (15), 5762. Available from: doi: 10.1073/pnas.0801353105.

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