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).