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

DOI: 10.1016/j.chembiol.2021.03.010 DOI Help

Authors: Jessica A. Cross (University of Bristol) , Magda S. Chegkazi (King's College London) , Roberto Steiner (King's College London; University of Padova) , Derek N. Woolfson (University of Bristol) , Mark P. Dodding (University of Bristol)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Chemical Biology , VOL 26

State: Published (Approved)
Published: April 2021

Abstract: 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.

Journal Keywords: peptide design; TPR domain; kinesin-1; intracellular transport; short linear motif; SLiM; microtubule transport; mash-up design

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography

Discipline Tags:

Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)