PMID- 28798389 OWN - NLM STAT- MEDLINE DCOM- 20190304 LR - 20190304 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 7 IP - 1 DP - 2017 Aug 10 TI - The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like Peptide 2, Exhibit Chaperone-like Activity. PG - 7802 LID - 10.1038/s41598-017-08372-5 [doi] LID - 7802 AB - Mitochondrial-derived peptides (MDPs) and their analogs have emerged as wide-spectrum, stress response factors protective in amyloid disease models. MDP cytoprotective functions are generally attributed to anti-apoptotic activity, however, little is known about their capacity to facilitate the cell's unfolded protein response via direct interactions with amyloidogenic proteins. Here, we explored the effects of the MDP-analog, humaninS14G (HNG), and the MDP, small humanin-like peptide 2 (SHLP2), on the misfolding of islet amyloid polypeptide (IAPP), a critical pathogenic step in type 2 diabetes mellitus (T2DM). Our thioflavin T fluorescence studies show that HNG inhibits IAPP misfolding at highly substoichiometric concentrations. Seeded fluorescence and co-sedimentation studies demonstrate MDPs block amyloid seeding and directly bind misfolded, seeding-capable IAPP species. Furthermore, our electron paramagnetic resonance spectroscopy and circular dichroism data indicate MDPs do not act by binding IAPP monomers. Taken together our results reveal a novel chaperone-like activity wherein these MDPs specifically target misfolded amyloid seeds to inhibit IAPP misfolding which, along with direct anti-apoptotic activity and beneficial metabolic effects, make HNG and SHLP2 exciting prospects as T2DM therapeutics. These data also suggest that other mitochondrial stress response factors within the MDP family may be amenable to development into therapeutics for protein-misfolding diseases. FAU - Okada, Alan K AU - Okada AK AD - Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, 90033, USA. FAU - Teranishi, Kazuki AU - Teranishi K AD - Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, 90033, USA. FAU - Lobo, Fleur AU - Lobo F AD - Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, 90033, USA. FAU - Isas, J Mario AU - Isas JM AD - Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, 90033, USA. FAU - Xiao, Jialin AU - Xiao J AD - University of Southern California Davis School of Gerontology, Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA, 90089-0191, USA. FAU - Yen, Kelvin AU - Yen K AD - University of Southern California Davis School of Gerontology, Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA, 90089-0191, USA. FAU - Cohen, Pinchas AU - Cohen P AD - University of Southern California Davis School of Gerontology, Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, CA, 90089-0191, USA. FAU - Langen, Ralf AU - Langen R AD - Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, 90033, USA. Langen@usc.edu. LA - eng GR - P01 AG034906/AG/NIA NIH HHS/United States GR - R01 NS084345/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170810 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (HNG peptide) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Islet Amyloid Polypeptide) SB - IM MH - Circular Dichroism MH - Diabetes Mellitus, Type 2/metabolism MH - Electron Spin Resonance Spectroscopy MH - Humans MH - Intracellular Signaling Peptides and Proteins/chemistry/*pharmacology MH - Islet Amyloid Polypeptide/*chemistry/metabolism MH - Microscopy, Electron, Transmission MH - Mitochondria/*chemistry MH - Protein Binding MH - Protein Folding/drug effects PMC - PMC5552803 COIS- A.K.O., K.T., F.L., J.M.I., J.X., and R.L. declare no competing financial interest. P.C. and K.Y. are consultants and P.C. is a stockholder of CohBar Inc. EDAT- 2017/08/12 06:00 MHDA- 2019/03/05 06:00 PMCR- 2017/08/10 CRDT- 2017/08/12 06:00 PHST- 2017/05/24 00:00 [received] PHST- 2017/07/11 00:00 [accepted] PHST- 2017/08/12 06:00 [entrez] PHST- 2017/08/12 06:00 [pubmed] PHST- 2019/03/05 06:00 [medline] PHST- 2017/08/10 00:00 [pmc-release] AID - 10.1038/s41598-017-08372-5 [pii] AID - 8372 [pii] AID - 10.1038/s41598-017-08372-5 [doi] PST - epublish SO - Sci Rep. 2017 Aug 10;7(1):7802. doi: 10.1038/s41598-017-08372-5.