Design of N-substituted Peptomer Ligands for EVH1 Domains

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2003; 278(38):36810-8. DOI: 10.1074/jbc.M305934200
Source: PubMed


Ena/VASP proteins are implicated in cytoskeletal reorganization during actin-dependent motility processes. Recruitment to
subcellular sites of actin polymerization is mediated by the highly conserved N-terminal EVH1 domain, which interacts with
target proteins containing proline-rich motifs. The VASP EVH1 domain specifically binds peptides with the consensus motif
FPPPP present in all its binding partners, including the Listerial ActA protein. Previous studies have shown that the Phe
and first and final Pro residues are highly conserved and cannot be substituted with any other natural amino acid without
significant loss of binding affinity. We have incorporated peptoid building blocks (sarcosine derived, non-natural amino acids)
into the peptide SFEFPPPPTEDEL from the Listerial ActA protein and were able to substitute the most highly conserved residues
of this motif while maintaining binding to the VASP EVH1 domain with affinities in the range of 45-180 μm. We then used NMR chemical shift perturbations to locate specific domain residues involved in particular interactions. These
studies may open up the way for designing selective modulators of VASP function for biological studies and for the development
of novel therapeutics for diseases involving pathologically altered cell adhesion or cell motility.

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Available from: Ronald Kühne, Jan 15, 2016
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