3.2 | Humanin and its disorder-to-order transition
Humanin is a secreted 24-amino acid polypeptide found in human serum that protects neurons from cell death in the presence of familial early onset-Alzheimer’s disease-associated mutants of amyloid precursor protein. Interestingly, the humanin coding sequence was mapped to a polyadenylated cDNA that was expressed in the surviving brain tissue of an Alzheimer’s disease patient, and is derived from the mitochondrial 16S ribosomal RNA (rRNA). Given that another mitochondrial peptide, MOTS-C, is encoded in a region overlapping the mitochondrial 12S rRNA, this raises the intriguing possibility that the mitochondrial rRNA genes may be polycistronic, though the molecular mechanisms by which microprotein-encoding transcripts are generated or processed are not yet defined. Humanin’s neuroprotective effects have been proposed to occur through multiple intracellular and cell-surface interaction partners, including BAX, IGFBP3, FPRL1, and CNTF Receptor α/WSX-1/gp130, though the relative contributions of these pathways to its in vivo activity remain to be determined. A circular dichroism and NMR study of humanin revealed that it does not adopt a stable secondary structure in aqueous solution, although through-space interactions consistent with turns at the N- and C-termini of the peptide were observed. In contrast, in 30% organic solvent, humanin forms an alpha helix spanning residues G5 to L18 (Figure 4D). This suggests that humanin may fold in hydrophobic environments such as cell membranes or in complex with interaction partners. Testing this hypothesis could provide deeper insight into its localization and associations with functional interaction partner(s).