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Cryo-EM captures early intermediate steps in dynein activation by LIS1

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Nguyen, Kendrick H. V., Karasmanis, Eva P., Kendrick, Agnieszka A., Reck-Peterson, Samara L., Leschziner, Andres E.·2025·Nature Communications
DOI 10.1038/s41467-025-62185-zPMC PMC12317079

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Abstract

Cytoplasmic dynein-1 (dynein) is an essential molecular motor in eukaryotic cells. Dynein primarily exists in an autoinhibited Phi state and requires conformational changes to assemble with its cofactors and form active transport complexes. LIS1, a key dynein regulator, enhances dynein activation and assembly. Using cryo-EM and a human dynein-LIS1 sample incubated with ATP, we map the conformational landscape of dynein activation by LIS1 and identify an early intermediate state that we propose precedes the previously identified dynein-LIS1 Chi state. Mutations that disrupt this species, which we termed “Pre-Chi”, lead to motility defects in vitro, emphasizing its functional importance. Together, our findings provide insights into how LIS1 relieves dynein autoinhibition during the activation pathway.

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Figures

Fig. 1 Conformational landscape of dynein activation by LIS1 in the presence of ATP. a Subunit and domain organization of full-length human dynein. Individual domains and accessory chains (heavy chain (HC), intermediate chain (IC), light intermediate chain (LIC), and three light chains (LC)) are color-coded, and these colors are used throughout the paper. b Schematic representation of a hypothetical pathway for dynein activation and assembly by LIS1. The numbers identify species—#1 Phi, #2 Chi, #3 assembly of transport complex, and #4, an active transport complex—that are discussed in the text. The asterisk in #3 indicates a LIS1-p150 dynactin interaction3, which is also discussed in the text. c Known LIS1 binding sites on dynein are shown on the Chi motor domain from panel (b). d Schematic representation of the cryo-EM sample preparation pipeline. e Distribution of particles corresponding to the three main species identified in the cryo-EM dataset: Phi, Pre-Chi, and Open. Representative 2D class averages are shown. In the case of Phi and Pre-Chi, representative 2D class averages of the dynein tails, which were processed separately, are shown above those for the motor domains. LIS1 is indicated whenever present in the averages. f Further processing identified six subclasses in the Open species. The particle distribution is indicated with the corresponding cryo-EM maps next to the section in the pie chart.
Fig. 1 Conformational landscape of dynein activation by LIS1 in the presence of ATP. a Subunit and domain organization of full-length human dynein. Individual domains and accessory chains (heavy chain (HC), intermediate chain (IC), light intermediate chain (LIC), and three light chains (LC)) are color-coded, and these colors are used throughout the paper. b Schematic representation of a hypothetical pathway for dynein activation and assembly by LIS1. The numbers identify species—#1 Phi, #2 Chi, #3 assembly of transport complex, and #4, an active transport complex—that are discussed in the text. The asterisk in #3 indicates a LIS1-p150 dynactin interaction3, which is also discussed in the text. c Known LIS1 binding sites on dynein are shown on the Chi motor domain from panel (b). d Schematic representation of the cryo-EM sample preparation pipeline. e Distribution of particles corresponding to the three main species identified in the cryo-EM dataset: Phi, Pre-Chi, and Open. Representative 2D class averages are shown. In the case of Phi and Pre-Chi, representative 2D class averages of the dynein tails, which were processed separately, are shown above those for the motor domains. LIS1 is indicated whenever present in the averages. f Further processing identified six subclasses in the Open species. The particle distribution is indicated with the corresponding cryo-EM maps next to the section in the pie chart.CC BY · PubMed Central
Fig. 2 Structure of the Pre-Chi dynein-LIS1 complex. a–c Cryo-EM maps and models of the motor and tail domains of the Pre-Chi dynein-LIS1 complex are shown in three orientations: (a) LIS1-free face, (b) LIS1-bound face, and (c) a top view where the Pre-Chi motors are shown enlarged and from the perspective of the tail. LIS1 is highlighted in the LIS1-bound (b) and top (c) views. d Local resolution map of Pre-Chi. e, f Nucleotide states of AAA1–AAA4 in Motor 2 (Heavy Chain 2, HC-2) (e) and Motor 1 (Heavy Chain 1, HC-1) (f).
Fig. 2 Structure of the Pre-Chi dynein-LIS1 complex. a–c Cryo-EM maps and models of the motor and tail domains of the Pre-Chi dynein-LIS1 complex are shown in three orientations: (a) LIS1-free face, (b) LIS1-bound face, and (c) a top view where the Pre-Chi motors are shown enlarged and from the perspective of the tail. LIS1 is highlighted in the LIS1-bound (b) and top (c) views. d Local resolution map of Pre-Chi. e, f Nucleotide states of AAA1–AAA4 in Motor 2 (Heavy Chain 2, HC-2) (e) and Motor 1 (Heavy Chain 1, HC-1) (f).CC BY · PubMed Central
Fig. 3 Phi-stabilizing contacts are disrupted in Pre-Chi. a Superposition of Pre-Chi (rainbow) and Phi (gray) models. HC-1 was used as the reference to align the models. Although the Pre-Chi model is shown from the LIS1-bound face, LIS1 was omitted for clarity. b Map of interatomic vectors connecting equivalent α carbons in Phi and Pre-Chi. The length of each vector is proportional to the distance between the atoms in Phi and Pre-Chi. c The four main interfaces between the motors in Phi are highlighted in the context of the boxed model in panel (a): Linker:Linker, Linker:AAA4, AAA5:AAA5, and Stalk:Stalk. d–g Close-ups of the three interfaces highlighted in (c) that are disrupted by the formation of Pre-Chi: Linker:Linker (d), AAA5:AAA5 (e), and Linker:AAA4 (f, g). The top panel corresponds to the Phi model, and the bottom panel corresponds to the Pre-Chi model. Key residues, motor chains, LIS1 ring, and the domain(s) of the motor being displayed are highlighted on each panel. Interactions are shown with dotted lines, with their distances (in Å) indicated. There was no significant change in the Stalk:Stalk interface. There are differences in the Linker:AAA4 interface between the LIS1-bound face (f) and the LIS1-free face (g).
Fig. 3 Phi-stabilizing contacts are disrupted in Pre-Chi. a Superposition of Pre-Chi (rainbow) and Phi (gray) models. HC-1 was used as the reference to align the models. Although the Pre-Chi model is shown from the LIS1-bound face, LIS1 was omitted for clarity. b Map of interatomic vectors connecting equivalent α carbons in Phi and Pre-Chi. The length of each vector is proportional to the distance between the atoms in Phi and Pre-Chi. c The four main interfaces between the motors in Phi are highlighted in the context of the boxed model in panel (a): Linker:Linker, Linker:AAA4, AAA5:AAA5, and Stalk:Stalk. d–g Close-ups of the three interfaces highlighted in (c) that are disrupted by the formation of Pre-Chi: Linker:Linker (d), AAA5:AAA5 (e), and Linker:AAA4 (f, g). The top panel corresponds to the Phi model, and the bottom panel corresponds to the Pre-Chi model. Key residues, motor chains, LIS1 ring, and the domain(s) of the motor being displayed are highlighted on each panel. Interactions are shown with dotted lines, with their distances (in Å) indicated. There was no significant change in the Stalk:Stalk interface. There are differences in the Linker:AAA4 interface between the LIS1-bound face (f) and the LIS1-free face (g).CC BY · PubMed Central
Fig. 4 Comparison of Pre-Chi with Chi. a Superposition between Chi and Pre-Chi. The model of human Chi from our previous work (dark gray)33 and human Pre-Chi motor (rainbow) were superimposed and aligned using HC-1. b Interatomic vectors connecting equivalent alpha carbons in Pre-Chi and Chi for the superposition shown in (a). c Pre-Chi model viewed from the LIS1-bound face with interfaces present in both Chi and Pre-Chi (#1-2 in black circles) and Pre-Chi-specific interfaces (#3-4 in red circles) highlighted. d Close-ups of the interfaces highlighted in (c). Residues involved in the interfaces and the names of the domains interacting with LIS1ring are highlighted in each panel. Interactions are shown with dotted lines, with their distances (in Å) indicated.
Fig. 4 Comparison of Pre-Chi with Chi. a Superposition between Chi and Pre-Chi. The model of human Chi from our previous work (dark gray)33 and human Pre-Chi motor (rainbow) were superimposed and aligned using HC-1. b Interatomic vectors connecting equivalent alpha carbons in Pre-Chi and Chi for the superposition shown in (a). c Pre-Chi model viewed from the LIS1-bound face with interfaces present in both Chi and Pre-Chi (#1-2 in black circles) and Pre-Chi-specific interfaces (#3-4 in red circles) highlighted. d Close-ups of the interfaces highlighted in (c). Residues involved in the interfaces and the names of the domains interacting with LIS1ring are highlighted in each panel. Interactions are shown with dotted lines, with their distances (in Å) indicated.CC BY · PubMed Central
Fig. 5 The Pre-Chi-specific contact between LIS1 and dynein’s linker is required for LIS1’s effect on dynein motility. a Representative kymographs from single-molecule motility assays with purified TMR–dynein–dynactin–BICD2 in the absence (white circle) or presence (black circle) of human LIS1 wild type or LIS1Δ298–308. Scale bars, 10 μm (x) and 100 s (y). b Single-molecule velocity (mean ± standard deviation of the means of each replicate) of TMR–dynein–dynactin–BICD2 complexes in the absence (white circles) or presence (black circles) of human LIS1 or LIS1Δ298–308. Superplots show all individual data points for each of the four technical replicates. n values for each replicate are: no LIS1, n = 70, 70, 50, 91; LIS1, n = 90, 85, 58, 117; LIS1Δ298–308, n = 116, 125, 89, 124. Larger shapes denote the mean of each of the four technical replicates. No LIS1 and LIS1 **P = 0.0017, Νο LIS1 and LIS1Δ298–308 ns P = 0.9692, LIS1 and LIS1Δ298–308 **P = 0.0012. Statistics were generated on the means of the four replicates using a One-Way ANOVA with Tukey’s multiple comparison test. c Superplots show Run frequencies (processive events /μm of microtubule length; mean ± standard deviation of the means of each replicate) of TMR–dynein–dynactin–BICD2 complexes in the absence (white circle) or presence (black circle) of unlabeled wild-type human LIS1 or LIS1Δ298–308. Data points are represented as triangles, circles, squares, and diamonds corresponding to single measurements within each technical replicate (no LIS1, n = 14, 12, 11, 8; LIS1, n = 12, 7, 7, 7; LIS1Δ298–308, n = 11, 5, 8, 9). No LIS1 and LIS1 **P = 0.005, LIS1 and LIS1Δ298–308 *P = 0.0466, no LIS1 and LIS1Δ298–308 ns P = 0.3453. Statistical analysis was done using a One-Way ANOVA with Tukey’s multiple comparison test. d Role of LIS1 in the activation of dynein. This schematic is an updated version of the pathway introduced in Fig. 1b that incorporates the Pre-Chi intermediate identified in this study. Source data for (b and c) are included with this manuscript, along with their corresponding statistical tests.
Fig. 5 The Pre-Chi-specific contact between LIS1 and dynein’s linker is required for LIS1’s effect on dynein motility. a Representative kymographs from single-molecule motility assays with purified TMR–dynein–dynactin–BICD2 in the absence (white circle) or presence (black circle) of human LIS1 wild type or LIS1Δ298–308. Scale bars, 10 μm (x) and 100 s (y). b Single-molecule velocity (mean ± standard deviation of the means of each replicate) of TMR–dynein–dynactin–BICD2 complexes in the absence (white circles) or presence (black circles) of human LIS1 or LIS1Δ298–308. Superplots show all individual data points for each of the four technical replicates. n values for each replicate are: no LIS1, n = 70, 70, 50, 91; LIS1, n = 90, 85, 58, 117; LIS1Δ298–308, n = 116, 125, 89, 124. Larger shapes denote the mean of each of the four technical replicates. No LIS1 and LIS1 **P = 0.0017, Νο LIS1 and LIS1Δ298–308 ns P = 0.9692, LIS1 and LIS1Δ298–308 **P = 0.0012. Statistics were generated on the means of the four replicates using a One-Way ANOVA with Tukey’s multiple comparison test. c Superplots show Run frequencies (processive events /μm of microtubule length; mean ± standard deviation of the means of each replicate) of TMR–dynein–dynactin–BICD2 complexes in the absence (white circle) or presence (black circle) of unlabeled wild-type human LIS1 or LIS1Δ298–308. Data points are represented as triangles, circles, squares, and diamonds corresponding to single measurements within each technical replicate (no LIS1, n = 14, 12, 11, 8; LIS1, n = 12, 7, 7, 7; LIS1Δ298–308, n = 11, 5, 8, 9). No LIS1 and LIS1 **P = 0.005, LIS1 and LIS1Δ298–308 *P = 0.0466, no LIS1 and LIS1Δ298–308 ns P = 0.3453. Statistical analysis was done using a One-Way ANOVA with Tukey’s multiple comparison test. d Role of LIS1 in the activation of dynein. This schematic is an updated version of the pathway introduced in Fig. 1b that incorporates the Pre-Chi intermediate identified in this study. Source data for (b and c) are included with this manuscript, along with their corresponding statistical tests.CC BY · PubMed Central

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Metadata

Authors
Nguyen, K. H. V., Karasmanis, E. P., Kendrick, A. A., Reck-Peterson, S. L., & Leschziner, A. E.
Affiliations
  • University of California San Diego (US)
  • Salk Institute for Biological Studies (US)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-08-01
Volume
16
Issue
1
Pages
7054-7054
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-62185-z
PMC
PMC12317079
OpenAlex
W4412818674
Cited by
5
References
1
Citations by year
2026: 5
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35 GM145296, T32 GM008326, R35 GM141825)
  • Jane Coffin Childs Memorial Fund for Medical Research
  • American Cancer Society
  • Howard Hughes Medical Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
cytoplasmic dynein-1, LIS1, dynein activation, molecular motors, motility defects
MeSH terms
Adenosine Triphosphate, Dyneins, Humans, Microtubule-Associated Proteins, Models, Molecular, Mutation, Protein Conformation, Cryoelectron Microscopy, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Cytoplasmic Dyneins

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