De novo designed transmembrane peptides activating the ?5?1 integrin.

ABSTRACT: Computationally designed transmembrane ?-helical peptides (CHAMP) have been used to compete for helix-helix interactions within the membrane, enabling the ability to probe the activation of the integrins ?IIb?3 and ?v?3. Here, this method is extended towards the design of CHAMP peptides that inhibit the association of the ?5?1 transmembrane (TM) domains, targeting the Ala-X3-Gly motif within ?5. Our previous design algorithm was performed alongside a new workflow implemented within the widely used Rosetta molecular modeling suite. Peptides from each computational approach activated integrin ?5?1 but not ?V?3 in human endothelial cells. Two CHAMP peptides were shown to directly associate with an ?5 TM domain peptide in detergent micelles to a similar degree as a ?1 TM peptide does. By solution-state nuclear magnetic resonance, one of these CHAMP peptides was shown to bind primarily the integrin ?1 TM domain, which itself has a Gly-X3-Gly motif. The second peptide associated modestly with both ?5 and ?1 constructs, with slight preference for ?5. Although the design goal was not fully realized, this work characterizes novel CHAMP peptides activating ?5?1 that can serve as useful reagents for probing integrin biology.

SUBMITTER: Mravic M 

PROVIDER: S-EPMC6151875 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature