Technologies that manipulate and augment the transport of vesicles and organelles by motor proteins along microtubules offer new routes to understanding its mechanistic basis, and could lead to therapeutics. Many cargoes for the kinesin-1 family of microtubule motors utilize adaptor proteins that harbor linear peptide motifs that are recognized by the tetratricopeptide repeats of kinesin light chains (KLCTPRs). These motifs bind with micromolar affinities at independent but overlapping sites. Here, we employ a fragment-linking peptide design strategy to generate an extended synthetic ligand (KinTag) with low nanomolar affinity for KLCTPRs. The X-ray crystal structure of the KLCTPR:KinTag complex demonstrates interactions as designed. Moreover, KinTag functions in cells to promote the transport of lysosomes with a high efficiency that correlates with its enhanced affinity. Together, these data demonstrate a new strategy for peptide design and its application to reveal that the more tightly a motor holds its cargo, the greater is the extent of cargo transport.

中文翻译：

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设计的高亲和力肽可劫持基于微管的转运

通过运动蛋白沿着微管操纵和增强囊泡和细胞器运输的技术为理解其机械基础提供了新途径，并可能导致治疗。驱动微管马达kinesin-1家族的许多货物都使用带有线性肽基序的衔接蛋白，这些基序被驱动蛋白轻链（KLCTPR）的四三肽重复序列识别。这些基序在独立但重叠的位点与微摩尔亲和力结合。在这里，我们采用片段连接肽设计策略来生成对KLCTPRs具有低纳摩尔亲和力的扩展合成配体（KinTag）。KLCTPR：KinTag复合物的X射线晶体结构证明了所设计的相互作用。此外，KinTag在细胞中起作用，以高效率促进溶酶体的运输，这与其增强的亲和力有关。这些数据加在一起证明了肽设计及其应用的新策略，以揭示电动机越紧紧地抓住货物，货物运输的范围就越大。