Structural basis for isoform-specific kinesin-1 recognition of Y-acidic cargo adaptors

Pernigo, S.; Chegkazi, Magda S.; Yip, Yan Yan; Treacy, Conor; Glorani, Giulia; Hansen, Kjetil; Politis, Argyris; Dodding, Mark P.; Steiner, Roberto A.

doi:10.1101/322057

Cited by 14 publications

(36 citation statements)

References 64 publications

(61 reference statements)

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“…Binding experiments and modeling suggest that SH2D6 might be a KLC1-binding partner. Altogether, JIP1, TorsinA, and SH2D6 accommodate into the TPR domain of KLC1 sharing the central consensus sequence [ (25) rightly named this latter the "Y-acidic" motif. However, differences are observed among these three proteins.…”

Section: Resultsmentioning

confidence: 99%

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Characterization of the binding mode of JNK-interacting protein 1 (JIP1) to kinesin-light chain 1 (KLC1)

Nguyen

Aumont-Niçaise

Andréani

et al. 2018

Journal of Biological Chemistry

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JIP1 was first identified as scaffold protein for the MAP kinase JNK and is a cargo protein for the kinesin1 molecular motor. JIP1 plays significant and broad roles in neurons, mainly as a regulator of kinesin1-dependent transport, and is associated with human pathologies such as cancer and Alzheimer disease. JIP1 is specifically recruited by the kinesin-light chain 1 (KLC1) of kinesin1, but the details of this interaction are not yet fully elucidated. Here, using calorimetry, we extensively biochemically characterized the interaction between KLC1 and JIP1. Using various truncated fragments of the tetratricopeptide repeat (TPR) domain of KLC1, we narrowed down its JIP1-binding region and identified seven KLC1 residues critical for JIP1 binding. These isothermal titration calorimetry (ITC)-based binding data enabled us to footprint the JIP1-binding site on KLC1-TPR. This footprint was used to uncover the structural basis for the marginal inhibition of JIP1 binding by the autoinhibitory LFP-acidic motif of KLC1, as well as for the competition between JIP1 and another cargo protein of kinesin1, the W-acidic motif-containing alcadein-α. Also, we examined the role of each of these critical residues of KLC1 for JIP1 binding in light of the previously reported crystal structure of the KLC1-TPR:JIP1 complex. Finally, sequence search in eukaryotic genomes identified several proteins, among which is SH2D6, that exhibit a motif similar to the KLC1-binding motif of JIP1. Overall, our extensive biochemical characterization of the KLC:JIP1 interaction, as well as identification of potential KLC1-binding partners, improves the understanding of how this growing family of cargos is recruited to kinesin1 by KLC1.

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Section: Resultsmentioning

confidence: 99%

“…(PDB code 6FUZ (25)), that of KLC1-TPR bound to the extreme C terminus of TorsinA (PDB code 6FV0 (25)), another KLC1binding partner (26), has been released at the same time. Of note, both crystal structures reveal that JIP1 and TorsinA share the same mode of binding to KLC1-TPR.…”

Section: Characterization Of the Jip1:klc1 Interaction Using Itcmentioning

confidence: 99%

Characterization of the binding mode of JNK-interacting protein 1 (JIP1) to kinesin-light chain 1 (KLC1)

Nguyen

Aumont-Niçaise

Andréani

et al. 2018

Journal of Biological Chemistry

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“…Our own work and that of others has identified identified two distinct classes of peptide sequences that are recognised by KLC TPR : tryptophan-acidic (W-acidic) motifs found in the lysosomal cargo adaptor SKIP as well as many others feature a tryptophan residue flanked by aspartic or glutamic acids in the consensus L/M-D/E-W-D/E (7,(11)(12)(13)(14)(15)(16); and Y-acidic motifs at the C termini of the axonal transport cargo adaptor JIP1 and Torsin A display a tyrosine residue flanked by acidic residues (17)(18)(19)(20). In mammals there are four closely related KLC isoforms (KLC1 -4).…”

Section: Introductionmentioning

confidence: 99%

“…In mammals there are four closely related KLC isoforms (KLC1 -4). Whilst Wacidic motifs typically bind both KLC1 TPR and KLC2 TPR , C-terminal Y-acidic motifs bind KLC1 TPR with a much higher affinity compared to KLC2 TPR (17,19,20). These motifs bind at distinct yet overlapping locations on the concave surface of the KLC TPR .…”

Section: Introductionmentioning

confidence: 99%

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A designed high-affinity peptide that hijacks microtubule-based transport

Cross

Chegkazi

Steiner

et al. 2020

Preprint

Self Cite

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ABSTRACTTechnologies 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.

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Motor–cargo adaptors at the organelle–cytoskeleton interface

Cross

Dodding

2019

Current Opinion in Cell Biology

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Cytoskeletal motors of the dynein, kinesin and myosin superfamilies maintain and adapt subcellular organelle organization to meet functional demands and support the vesicular transport of material between organelles. These motors require the capacity to specifically recognize the vesicle/organelle to be transported and are capable of selective recognition of multiple cargo. Recent studies have begun to uncover the molecular basis for motor recruitment and have highlighted the role of organelle-associated 'cargo-adaptor' proteins in cellular transport. These adaptors possess sequences and/or structural features that enable both motor recruitment and activation from regulated, inactive, states to enable motility on the cytoskeleton. Motor-cargo adaptor interactions define a key organelle-cytoskeleton interface, acting as crucial regulatory hubs to enable the cell to finely control membrane trafficking and organelle dynamics. Understanding the molecular basis of these interactions may offer new opportunities to control and manipulate cytoskeletal and organelle dynamics for the development of new research tools and potentially therapeutics.

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Structural basis for isoform-specific kinesin-1 recognition of Y-acidic cargo adaptors

Cited by 14 publications

References 64 publications

Characterization of the binding mode of JNK-interacting protein 1 (JIP1) to kinesin-light chain 1 (KLC1)

Characterization of the binding mode of JNK-interacting protein 1 (JIP1) to kinesin-light chain 1 (KLC1)

A designed high-affinity peptide that hijacks microtubule-based transport

Motor–cargo adaptors at the organelle–cytoskeleton interface

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