Abstract
Intrinsically disordered proteins (IDPs) have been in the spotlight for their unique properties, such as their lack of secondary structures and low sequence complexity. Alpha-synuclein and tau are representative disease-related IDPs with low complexity regions in their sequences, accumulating in the brains of patients with Parkinson disease and Alzheimer disease, respectively. Their heat resistance in particular was what attracted our attention. We assumed that there exist many other unidentified proteins that are resistant to heat-treatment, referred to as heat-stable proteins, which would also have low sequence complexity. In this study, we performed proteomic analysis of heat-stable proteins of mouse brains and found that proteins with compositionally biased regions are abundant in the heat-stable proteins. The proteins related to neurodegeneration are known to undergo different types of post-translational modifications (PTMs) such as phosphorylation and ubiquitination. We then investigated the heat-stability and aggregation properties of phosphorylated synuclein and tau with different phosphorylation sites. We suggest that PTMs can be important factors that determine the heat-stability and aggregation properties of a protein. IDPs identified in the heat-stable proteins of mouse brains would be candidates for the pathogenic proteins for neurodegeneration.
Highlights
Disordered proteins (IDPs) have been in the spotlight for their unique properties, such as their lack of secondary structures and low sequence complexity
We investigated whether the presence or absence of low complexity regions (LCRs) has any relationship with the existence of compositionally biased regions (CBRs) in protein sequences (Fig. 2D)
The cores of globular proteins are rich in hydrophobic amino acids that stabilize the protein structures, while the surfaces of globular proteins are rich in polar and charged amino acids that interact favorably with water
Summary
Disordered proteins (IDPs) have been in the spotlight for their unique properties, such as their lack of secondary structures and low sequence complexity. Alpha-synuclein and tau are representative disease-related IDPs with low complexity regions in their sequences, accumulating in the brains of patients with Parkinson disease and Alzheimer disease, respectively. Their heat resistance in particular was what attracted our attention. It is assumed that long (> 30 residues) disordered segments are found to occur in 33% of eukaryotic proteins, and 22% of human disease mutations occur in IDRs7, which are frequently associated with various human diseases such as genetic diseases, diabetes and neurodegenerative d iseases[8,9] These proteins with IDRs can undergo different types of PTMs such as phosphorylation, ubiquitination and acetylation, which can lead to pathological situations due to the modulation of their normal functions[10,11]. It has been established that GSK-3 is implicated in the formation of aberrant tau aggregates in certain mouse m odels[25,26]
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