This title appears in the Scientific Report :
2018
Please use the identifier:
http://hdl.handle.net/2128/21063 in citations.
Please use the identifier: http://dx.doi.org/10.1016/j.compchemeng.2018.02.013 in citations.
Elucidating the multi-targeted anti-amyloid activity and enhanced islet amyloid polypeptide binding of β-wrapins
Elucidating the multi-targeted anti-amyloid activity and enhanced islet amyloid polypeptide binding of β-wrapins
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 recogni...
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Personal Name(s): | Orr, Asuka A. |
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Shaykhalishahi, Hamed / Mirecka, Ewa A. / Jonnalagadda, Sai Vamshi R. / Hoyer, Wolfgang (Corresponding author) / Tamamis, Phanourios (Corresponding author) | |
Contributing Institute: |
Strukturbiochemie; ICS-6 |
Published in: | Computers & chemical engineering, 116 (2018) S. 322 - 332 |
Imprint: |
Amsterdam [u.a.]
Elsevier Science
2018
|
PubMed ID: |
30405276 |
DOI: |
10.1016/j.compchemeng.2018.02.013 |
Document Type: |
Journal Article |
Research Program: |
Physical Basis of Diseases |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1016/j.compchemeng.2018.02.013 in citations.
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. |