The study shows that the human peptide humanin can clump together into beta‑sheet fibrils, and that certain mutations stop this clumping and also reduce its ability to leave cells and block cell death. This means the peptide’s shape matters for how well it works and how it should be given as a supplement or drug.

Humanin is an endogenous human peptide with cytoprotective effects, including inhibition of apoptosis via interaction with BCL-2 proteins such as BAX. The therapeutic benefits of HN have been well-documented, and administering humanin and related endogenous human peptides for treatment of disease, aging, and enhancement of athletic performance is becoming more widespread. However, very little is known about the actual molecular structure of humanin and how it interacts with its protein partners. Here we present the amyloid-like β-sheet fibrillization of HN along with characterization of its secondary structure properties via transmission electron microscopy and other biophysical techniques. We identified several important HN mutants and documented their effects on the fibrillization process. Mutants that display inhibited β-sheet fibrillization were associated with those previously identified to be secretion deficient in vitro, highlighting the importance of β-sheet structure for membrane interactions. Successful β-sheet structural transitions are also required for productive interactions with BCL-2 family proteins resulting in apoptosis inhibition. Implications of fibrillization on the administration of HN is discussed.