Abstract
Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with hyperglycemia (high blood sugar) related to either insulin resistance or insufficient insulin production. Among the various molecular events and players implicated in the manifestation and development of diabetes mellitus, proteins play several important roles. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database has information on 34 human proteins experimentally shown to be related to the T2DM pathogenesis. It is known that many proteins associated with different human maladies are intrinsically disordered as a whole, or contain intrinsically disordered regions. The presented study shows that T2DM is not an exception to this rule, and many proteins known to be associated with pathogenesis of this malady are intrinsically disordered. The multiparametric bioinformatics analysis utilizing several computational tools for the intrinsic disorder characterization revealed that IRS1, IRS2, IRS4, MAFA, PDX1, ADIPO, PIK3R2, PIK3R5, SoCS1, and SoCS3 are expected to be highly disordered, whereas VDCC, SoCS2, SoCS4, JNK9, PRKCZ, PRKCE, insulin, GCK, JNK8, JNK10, PYK, INSR, TNF-α, MAPK3, and Kir6.2 are classified as moderately disordered proteins, and GLUT2, GLUT4, mTOR, SUR1, MAPK1, IKKA, PRKCD, PIK3CB, and PIK3CA are predicted as mostly ordered. More focused computational analyses and intensive literature mining were conducted for a set of highly disordered proteins related to T2DM. The resulting work represents a comprehensive survey describing the major biological functions of these proteins and functional roles of their intrinsically disordered regions, which are frequently engaged in protein–protein interactions, and contain sites of various posttranslational modifications (PTMs). It is also shown that intrinsic disorder-associated PTMs may play important roles in controlling the functions of these proteins. Consideration of the T2DM proteins from the perspective of intrinsic disorder provides useful information that can potentially lead to future experimental studies that may uncover latent and novel pathways associated with the disease.
Highlights
Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, inefficiency of insulin action, or both
IRS2, MAFA, IRS1, PDX1, IRS4, ADIPO, PIK3R5, SoCS1, PIK3R2, and SoCS3 were predicted as highly disordered, VDCC, SoCS4, PRKCE, SoCS2, JNK9, PRKCZ, insulin, GCK, JNK10, JNK8, PYK, insulin receptor (INSR), t.umor necrosis factor (TNF)-α, MAPK3, and Kir6.2 were classified as moderately disordered proteins, whereas GLUT4, mTOR, SUR1, MAPK1, IKKA, GLUT2, PRKCD, PIK3CB, and PIK3CA were predicted as mostly ordered
This work was dedicated to the computational analysis of several proteins from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database that have been experimentally shown to be involved in Type 2 Diabetes Mellitus (T2DM)
Summary
Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, inefficiency of insulin action, or both. The subcellular localization, function, and likely stability of the β-cell enriched transcription factors were found to be made up of T2DM [17] The loss of these central factors leads to significant reductions in the expression of their gene targets, including insulin, solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2), and glucagon-like peptide 1 receptor (GLP1R), all of which are critical to β-cell glucose-sensing and insulin secretion [17]. The intrinsic lack of structure in IDPs and IDPRs provides several functional advantages that make them ideally suited for mediation of the processes related to transcriptional regulation.
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