The membrane-active amphibian peptide caerin 1.8 inhibits fibril formation of amyloid β1-42

Yanqin Liu; Tianfang Wang; Antonio N Calabrese; John A Carver; Scott F Cummins; John H Bowie

doi:10.1016/j.peptides.2015.08.004

The membrane-active amphibian peptide caerin 1.8 inhibits fibril formation of amyloid β1-42

Peptides. 2015 Nov:73:1-6. doi: 10.1016/j.peptides.2015.08.004. Epub 2015 Aug 11.

Authors

Yanqin Liu¹, Tianfang Wang², Antonio N Calabrese¹, John A Carver³, Scott F Cummins², John H Bowie⁴

Affiliations

¹ Department of Chemistry, The University of Adelaide, South Australia 5005, Australia.
² Genecology Research Centre, University of the Sunshine Coast, Maroochydore DC, Queensland 4558, Australia.
³ Research School of Chemistry, The Australian National University, Canberra, Australian Capital Chemistry, 2601, Australia.
⁴ Department of Chemistry, The University of Adelaide, South Australia 5005, Australia. Electronic address: john.bowie@adelaide.edu.au.

PMID: 26275335
DOI: 10.1016/j.peptides.2015.08.004

Abstract

The amphibian host-defense peptide caerin 1.8 [(1)GLFKVLGSV(10)AKHLLPHVVP(20)VIAEKL(NH2)] inhibits fibril formation of amyloid β 1-42 [(1)DAEFRHDSG(10)YEVHHQKLVF(20)FAEDVGSNKG(30)AIIGLMVGGV(40)VIA] [Aβ42] (the major precursor of the extracellular fibrillar deposits of Alzheimer's disease). Some truncated forms of caerin 1.8 also inhibit fibril formation of Aβ42. For example, caerin 1.8 (1-13) [(1)GLFKVLGSV(10)AKHL(NH2) and caerin 1.8 (22-25) [KVLGSV(10)AKHLLPHVVP(20)VIAEKL(NH2)] show 85% and 75% respectively of the inhibition activity of the parent caerin 1.8. The synthetic peptide KLVFFKKKKKK is a known inhibitor of Aβ42 fibril formation, and was used as a standard in this study. Caerin 1.8 is the more effective fibril inhibitor. IC50 values (± 15%) are caerin 1.8 (75 μM) and KLVFFKKKKKK (370 μM). MALDI mass spectrometry shows the presence of a small peak corresponding to a protonated 1:1 adduct [caerin 1.8/Aβ42]H(+). Molecular dynamics simulation suggests that both hydrogen bonding and hydrophobic interactions between Aβ42 and caerin 1.8 facilitate the formation of a 1:1 complex in water. Fibril formation from Aβ42 has been proposed to be based around the (16)KLVF(20)F region of Aβ42; this region in the 1:1 complex is partially blocked from attachment of a further molecule of Aβ42.

Keywords: Alzheimer’s disease; Amyloid beta 1-42 (Aβ42); Amyloid fibrils; Caerin 1.8, an Aβ42 fibrilisation inhibitor; MALDI mass spectrometry: 1:1 adduct; MD simulation of 1:1 adduct in water; [Aβ42/caerin 1.8]H+.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amphibian Proteins / chemistry*
Amyloid / chemistry*
Amyloid beta-Peptides / chemistry*
Antimicrobial Cationic Peptides / chemistry*
Humans
Molecular Dynamics Simulation*
Peptide Fragments / chemistry*
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / methods

Substances

Amphibian Proteins
Amyloid
Amyloid beta-Peptides
Antimicrobial Cationic Peptides
Peptide Fragments
amyloid beta-protein (1-42)
caerin 1.8 protein, Litoria