Potential of ADAM 17 Signal Peptide To Form Amyloid Aggregates in Vitro.

Taniya Bhardwaj, Rajanish Giri

ACS chemical neuroscience 2023 Oct 18

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ADAM 17, a disintegrin and metalloproteinase 17 belonging to the adamalysin protein family, is a Zn2+-dependent type-I transmembrane α-secretase protein. As a major sheddase, ADAM 17 acts as an indispensable regulator of chief cellular events and controls diverse cytokines, adhesion molecules, and growth factors. The signal peptide (residues 1-17) of ADAM 17 targets the protein to the secretory pathway and gets cleaved off afterward. No other function is documented for the ADAM 17 signal peptide (ADAM 17-SP) inside the cells. Here, we have taken a reductionist approach to understand the biophysical properties of ADAM 17-SP. Aiming to understand the possibility of aggregation, we found several aggregation-prone segments in the signal peptide. We performed in vitro experiments to show that the signal peptide forms amyloid-like aggregates in buffered conditions. We also studied its aggregation in the presence of sodium tripolyphosphate and heparin to correlate with the cellular conditions, as these biomolecules are naturally present inside cells. Further, we performed seeding experiments to observe the possibility of ADAM 17-SP aggregate interaction with the Aβ42 peptide. The results suggest that its seeds escalate the aggregation kinetics of the Aβ42 peptide and form heteromeric aggregates with it. We believe this finding could further intensify the aggregation studies on other signal peptides and shed light on the potential role of these segments other than signaling.

Citation

Taniya Bhardwaj, Rajanish Giri. Potential of ADAM 17 Signal Peptide To Form Amyloid Aggregates in Vitro. ACS chemical neuroscience. 2023 Oct 18;14(20):3818-3825