Protein aggregation profile of the human kinome

Abstract

Protein aggregation into amyloid fibrils is associated with the onset of an increasing number of human disorders, including Alzheimer's disease, diabetes, and some types of cancer. The ability to form toxic amyloids appears to be a property of most polypeptides. Accordingly, it has been proposed that reducing aggregation and its effect in cell fitness is a driving force in the evolution of proteins sequences. This control of protein solubility should be especially important for regulatory hubs in biological networks, like protein kinases. These enzymes are implicated in practically all processes in normal and abnormal cell physiology, and phosphorylation is one of the most frequent protein modifications used to control protein activity. Here, we use the AGGRESCAN algorithm to study the aggregation propensity of kinase sequences. We compared them with the rest of globular proteins to decipher whether they display differential aggregation properties. In addition, we compared the human kinase complement with the kinomes of other organisms to see if we can identify any evolutionary trend in the aggregational properties of this protein superfamily. Our analysis indicates that kinase domains display significant aggregation propensity, a property that decreases with increasing organism complexity.

Aggregation prone regions in human proteome: Insights from large‐scale data analyses

“…Even when the native protein structure is perturbed and these segments become solvent exposed, they still tend to promote local structural order by self‐associating to nucleate and propagate cross‐β steric zipper motifs that may eventually lead to highly ordered fibrillary structures. Several of these order promoting properties of the APRs have been also reported in earlier studies …”

“…Protein aggregation often results in protein inactivation . Recent surveys of monomeric protein structures suggested that APRs are found close to enzyme catalytic sites . Here, the distribution of TANGO and WALTZ predicted APRs around the active and binding sites in 587 protein chains was analysed by calculating the distances between active or binding site residues and the residues found in the APRs.…”

“…Several of these order promoting properties of the APRs have been also reported in earlier studies. 8,10,38,84 A limitation of this study is the absence of a large number of experimentally known aggregating peptides to scan against the human proteome. To overcome this limitation, we have used two widely used APR prediction programs, namely, TANGO and WALTZ.…”

“…More importantly, this survey finds that no single strategy for mitigating the deleterious effects of the APRs has been favoured by the human proteome. Instead, human proteome has been versatile and has simultaneously utilized almost all the known strategies reported in the literature . Moreover, the same sequence‐structural optimizations, which minimize the threat of aggregation to human proteins, simultaneously enable the human proteome to utilize conformational order promoting features of the APRs toward stabilizing native protein folds, preventing un‐intended aggregation upon post‐translational modifications, and to optimize structural dynamics required for biochemical function.…”

Biophysical Characterisation of Calumenin as a Charged F508del-CFTR Folding Modulator

“…The composition of different protein sequences in our dataset has been deduced using various parameters such as hydropathy (GRAVY), unfoldability, aggregation propensity, instability, charge and disorder by applying bioinformatics based prediction tools such as ProtParam [24] , FoldIndex [25] , IUPRED [26] , [27] and Aggrescan [28] . These tools have proved valuable in characterizing the functions of numerous novel proteins in the past [45] – [48] .…”