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Publication Abstract from PubMed

Synthetic peptides are attractive candidates to manipulate protein-protein interactions inside the cell as they mimic natural interactions to compete for binding. However, protein-peptide interactions are often dynamic and weak. A challenge is to design peptides that make improved interactions with the target. Here, we devise a fragment-linking strategy-"mash-up" design-to deliver a high-affinity ligand, KinTag, for the kinesin-1 motor. Using structural insights from natural micromolar-affinity cargo-adaptor ligands, we have identified and combined key binding features in a single, high-affinity ligand. An X-ray crystal structure demonstrates interactions as designed and reveals only a modest increase in interface area. Moreover, when genetically encoded, KinTag promotes transport of lysosomes with higher efficiency than natural sequences, revealing a direct link between motor-adaptor binding affinity and organelle transport. Together, these data demonstrate a fragment-linking strategy for peptide design and its application in a synthetic motor ligand to direct cellular cargo transport.

Fragment-linking peptide design yields a high-affinity ligand for microtubule-based transport.,Cross JA, Chegkazi MS, Steiner RA, Woolfson DN, Dodding MP Cell Chem Biol. 2021 Mar 31. pii: S2451-9456(21)00149-5. doi:, 10.1016/j.chembiol.2021.03.010. PMID:33838110^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.