Structural Biochemistry/Intrinsically Disordered Proteins: 10-year recap/Structural Disorder in Disease
Structural Disorder in Disease[edit | edit source]
A decade ago, scientists made the conclusion that structural disorder had a role in diseases, because of its important properties and characteristics in cellular function. Structural disorder was “then confirmed and/or studied in great detail in many other important disease-associated proteins, such as p53, T protein, and cystic fibrosis transmembrane conductance regulator (CFTR), and was also substantiated by several genome-scale bioinformatics studies”.[1] Studies have shown that a high level of structural disorder was found in proteins that are involved in cancer, neurodegenerative diseases, cardiovascular diseases, and diabetes, leading to the creation of disorder in diseases. “A comprehensive bioinformatics analysis of 406 human proteins, such as breakpoint cluster region-Abelson leukemia (Bcr-Abl) and CBP-mixed lineage leukemia (CBP-MLL), which are both generated by chromosomal translocation and gene fusion in cancer, substantiated the hypothesis that structural disorder enables the cellular existence of oncogenic protein chimeras”.[1] The negativity of structural disorder can appear in dosage sensitivity of genes that cause irregularties if overexpressed. This issue “might be linked with the binding promiscuity of intrinsically disordered proteins, which can be restrained only by their tight regulation at the transcriptional, RNA and protein levels”.[1] Regulation is needed f or control.
Structural disorder is used in the formation of insoluble and intractable substances, known as amyloids. “As a result of the structural exposure of their polypeptide chain, amyloidogenic proteins, which can either cause disease or a heritable advantageous change in phenotype, have a high level of disorder”.[1] Proteins that are rich in the amino acids glycogen and asparagin have the ability to form amyloids: “Asn promotes assembly of potentially functional self-templating amyliods, whereas richness in Gln seems to favor the formation of toxic nonamyloid conformers”.[1]
Structural disorder is important in the action of pathogens. For example, virus entry, replication, and budding are determined by deregulating the signaling of the host cell, which is applied through interactions of viral proteins with key host regulatory proteins. “In most cases viruses use motif-mimicry for this purpose, that is, short motifs in disordered regions mimicking host protein SLIMs”.[1] As an example, “adenovirus early region 1A (E1A) oncoprotein (pRb) into a tertiary pRb:E1A:CBP complex that overrides the cell-cycle checkpoints of the host”.[1]
The studies of intrinsically disordered proteins are viable for the understanding of the cause and development of disease states. In hopes to develop cures and remedies, these disordered proteins are examined thoroughly.