Fragment-linking peptide design yields a high-affinity ligand for microtubule-based transport

Jessica A. Cross, Magda S. Chegkazi, Roberto A. Steiner*, Derek N. Woolfson, Mark P. Dodding

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1347-1355.e5
JournalCell Chemical Biology
Issue number9
Publication statusPublished - 16 Sept 2021


  • intracellular transport
  • kinesin-1
  • mash-up design
  • microtubule transport
  • peptide design
  • short linear motif
  • SLiM
  • TPR domain


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