The role of glycine-rich region in driving specificity of JDP/Hsp70 chaperone systems

Cameron Young, Baher Boktor, Erina Kotreli and Szymon Ciesielski

Department of Chemistry and Biochemistry, University of North Florida

Molecular chaperones are a subset of cellular proteins dedicated to facilitating the folding and maintenance of the structural integrity of virtually all other cellular proteins. They also constitute the main cellular defense mechanism against stress-induced protein misfolding and aggregation. Numerous human diseases are associated with aggregation of structurally abnormal proteins in the form of ordered amyloid fibrils, like the amyloid-b and tau in Alzheimer’s or a-synuclein in Parkinson’s disease. Recent studies emphasized unique structural features of the human molecular chaperone system, composed of Hsp70 and its obligatory partner, J-domain protein (JDP) DNAJB1, governing their ability to fragment amyloid fibrils. In our comparative study, we investigated these structural features of JDPs in a broader context of their biological functions. More specifically, using yeast S. cerevisiae as a model, we compared the biological relevance of conserved amino acids found in a low-complexity glycine-rich region of both class A and class B JDPs. In combination with bioinformatic analysis, we were able to identify an essential motif found in both types of JDPs and dissect its structural similarities and differences between the JDP classes using NMR. Obtained data indicates that the identified JDP region can serve as an additional interaction site with Hsp70, presumably fine-tuning its activity to process unique substrates like amyloid fibrils. This recently published comparative study as well as ongoing investigation further exploring the emerging novel interaction site, provides new insights into the mechanism of JDP/Hsp70 activity, especially relevant to human protein conformational disorders.