Structural Basis of the High Affinity Interaction between the Alphavirus Nonstructural Protein-3 (nsP3) and the SH3 Domain of Amphiphysin-2
Tossavainen, H., Aitio, O., Hellman, M., Saksela, K., & Permi, P. (2016). Structural Basis of the High Affinity Interaction between the Alphavirus Nonstructural Protein-3 (nsP3) and the SH3 Domain of Amphiphysin-2. Journal of Biological Chemistry, 291(31), 16307-16317. https://doi.org/10.1074/jbc.M116.732412
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Journal of Biological ChemistryDate
2016Discipline
Solu- ja molekyylibiologiaOrgaaninen kemiaNanoscience CenterCell and Molecular BiologyOrganic ChemistryNanoscience CenterCopyright
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published in this repository with the kind permission of the publisher.
We show that a peptide from Chikungunya virus nsP3 protein
spanning residues 1728–1744 binds the amphiphysin-2 (BIN1)
Src homology-3 (SH3) domain with an unusually high affinity
(Kd 24 nM). Our NMR solution complex structure together with
isothermal titration calorimetry data on several related viral and
cellular peptide ligands reveal that this exceptional affinity originates
from interactions between multiple basic residues in the
target peptide and the extensive negatively charged binding surface
of amphiphysin-2 SH3. Remarkably, these arginines show
no fixed conformation in the complex structure, indicating that
a transient or fluctuating polyelectrostatic interaction accounts
for this affinity. Thus, via optimization of such dynamic electrostatic
forces, viral peptides have evolved a superior binding
affinity for amphiphysin-2 SH3 compared with typical cellular
ligands, such as dynamin, thereby enabling hijacking of
amphiphysin-2 SH3-regulated host cell processes by these
viruses. Moreover, our data show that the previously described
consensus sequence PXRPXR for amphiphysin SH3 ligands is
inaccurate and instead define it as an extended Class II binding
motif PXXPXRpXR, where additional positive charges between
the two constant arginine residues can give rise to extraordinary
high SH3 binding affinity.
...
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