Protein misfolding and amyloid formation is an underlying pathological hallmark in a number of prevalent diseases of protein aggregation, including Parkinson's disease, Alzheimer's disease and Type 2 diabetes (T2D). The expansion in the prevalence of T2D, including in Qatar, where a high percentage of the population is affected by diabetes, poses considerable risks to individuals, the healthcare system and the economy. Epidemiological studies reveal that up to 95% of all patients with T2D are shown to have pancreatic amyloid deposits, as detected in post-mortem studies. Most importantly, the severity of the disease appears to correlate with the degree of the deposition of IAPP aggregates. The misfolding of IAPP followed by the aggregation has been shown to be highly cytotoxic and to play a key role in the death of β-cells in T2D. Thus, the modulation of the aggregation process, promoting the proper folding of IAPP, may be considered as an attractive avenue for a therapeutic intervention. Indeed, molecular chaperones have been shown to suppress the misfolding and to prevent amyloid formation. The mechanism of how Hsc70 inhibits hIAPP fibril formation is complex and is not yet fully understood. It remains unclear how specific domains of Hsc70 function independently or in cohort to produce the observed inhibition of fibril formation of hIAPP. To address these questions, we used the power of in vitro methods to dissect out the relative contribution of the different Hsc70 structural domains, by investigating the effect of a series of deletion mutants of Hsc70 on hIAPP fibril formation. We also investigated in further detail the mode and mechanism of interaction between Hsc70 and hIAPP. The results indicate that Hsc70 can bind to hIAPP and delay fibril formation even in the absence of the ATPase domain, but interaction of hIAPP with the substrate- binding domain is strongly influenced by the C-terminal lid region. Determining the molecular interplay between hIAPP and molecular chaperone Hsc70 will provide the basis for designing modulators of IAPP aggregation.


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