TY  - JOUR
AU  - Orr, Asuka A.
AU  - Shaykhalishahi, Hamed
AU  - Mirecka, Ewa A.
AU  - Jonnalagadda, Sai Vamshi R.
AU  - Hoyer, Wolfgang
AU  - Tamamis, Phanourios
TI  - Elucidating the multi-targeted anti-amyloid activity and enhanced islet amyloid polypeptide binding of β-wrapins
JO  - Computers & chemical engineering
VL  - 116
SN  - 0098-1354
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - FZJ-2018-07289
SP  - 322 - 332
PY  - 2018
AB  - β-wrapins are engineered binding proteins stabilizing the β-hairpin conformations of amyloidogenic proteins islet amyloid polypeptide (IAPP), amyloid-β, and α-synuclein, thus inhibiting their amyloid propensity. Here, we use computational and experimental methods to investigate the molecular recognition of IAPP by β-wrapins. We show that the multi-targeted, IAPP, amyloid-β, and α-synuclein, binding properties of β-wrapins originate mainly from optimized interactions between β-wrapin residues and sets of residues in the three amyloidogenic proteins with similar physicochemical properties. Our results suggest that IAPP is a comparatively promiscuous β-wrapin target, probably due to the low number of charged residues in the IAPP β-hairpin motif. The sub-micromolar affinity of β-wrapin HI18, specifically selected against IAPP, is achieved in part by salt-bridge formation between HI18 residue Glu10 and the IAPP N-terminal residue Lys1, both located in the flexible N-termini of the interacting proteins. Our findings provide insights towards developing novel protein-based single- or multi-targeted therapeutics.
LB  - PUB:(DE-HGF)16
C6  - pmid:30405276
UR  - <Go to ISI:>//WOS:000448410000023
DO  - DOI:10.1016/j.compchemeng.2018.02.013
UR  - https://juser.fz-juelich.de/record/858403
ER  -