Therapeutic Interventions of Cancers Using Intrinsically Disordered Proteins as Drug Targets: c-Myc as Model System

Abstract

The concept of protein intrinsic disorder has taken the driving seat to understand regulatory proteins in general. Reports suggest that in mammals nearly 75% of signalling proteins contain long disordered regions with greater than 30 amino acid residues. Therefore, intrinsically disordered proteins (IDPs) have been implicated in several human diseases and should be considered as potential novel drug targets. Moreover, intrinsic disorder provides a huge multifunctional capability to hub proteins such as c-Myc and p53. c-Myc is the hot spot for understanding and developing therapeutics against cancers and cancer stem cells. Our past understanding is mainly based on in vitro and in vivo experiments conducted using c-Myc as whole protein. Using the reductionist approach, c-Myc oncoprotein has been divided into structured and disordered domains. A wealth of data is available dealing with the structured perspectives of c-Myc, but understanding c-Myc in terms of disordered domains has just begun. Disorderness provides enormous flexibility to proteins in general for binding to numerous partners. Here, we have reviewed the current progress on understanding c-Myc using the emerging concept of IDPs.

Intrinsically Disordered Proteins (Idps) in Human Diseases: A Review

“…Disorder prediction studies show that the C-terminal region (410-490) of c-Myc is the most conserved region in protein disorder pattern and in the absence of binding partner the N-terminal region is also unstructured. Computational and experimental researches have shown that c-Myc extensively uses its disorder regions to perform diverse interactions 30 . Deregulation of the c-Myc transcription factor is involved in almost 50% of human cancers 19,30 .…”

“…Computational and experimental researches have shown that c-Myc extensively uses its disorder regions to perform diverse interactions 30 . Deregulation of the c-Myc transcription factor is involved in almost 50% of human cancers 19,30 . A high percentage of cancer-associated proteins have long disordered regions 29 .…”

Understanding the penetrance of intrinsic protein disorder in rotavirus proteome

“…In recent studies, it is reported that several IDPs/IDPRs display disorder-toorder transitions after interaction with their partners [23]. For example, the intrinsically disordered transactivation domain of c-Myb attains an a-helical conformation after association with KIX [24][25][26][27], whereas C-terminal regulatory domain of p53 oncoprotein undergoes transitions from its disordered form into a-helical, b-structural, or two irregular forms with different configurations at binding to Cyclin A, Sirtuin, CBP, and the S100bb dimer [23,28]. To enable such folding at binding interactions with their partners, many IDPs/IDPRs are equipped with molecular recognition features (MoRFs) [29,30], which are short disorder-based binding regions that regulate the functional mechanism under physiological conditions.…”

How Do We Study the Dynamic Structure of Unstructured Proteins: A Case Study on Nopp140 as an Example of a Large, Intrinsically Disordered Protein

“…Although these IDPs lack a well-folded domain structure, they have several motifs that can serve as interaction sites with other biomolecules, such as DNA, RNA, or protein [ 5 ]. Previous studies have indicated that these interactions are associated with numerous biological functions and human disorders [ 6 , 7 , 8 ]. During interactions with target proteins, IDPs, particularly IDRs, may undergo conformational changes.…”