scholarly journals Structural Basis for Cytoplasmic Dynein-1 Regulation by Lis1

2021 ◽  
Author(s):  
John P Gillies ◽  
Janice M Reimer ◽  
Eva P Karasmanis ◽  
Indrajit Lahiri ◽  
Zaw Min Htet ◽  
...  
Keyword(s):  
High Resolution ◽  
Cytoplasmic Dynein ◽  
Motor Domain ◽  
Structural Basis ◽  
Neurodevelopmental Disease ◽  
Microtubule Motor ◽  
High Resolution Structure ◽  
Resolution Structure

The lissencephaly 1 gene, LIS1, is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator that binds directly to dynein's motor domain, and by doing so alters dynein's mechanochemistry. Lis1 is required for the formation of fully active dynein complexes, which also contain essential cofactors: dynactin and an activating adaptor. Here, we report the first high-resolution structure of the yeast dynein-Lis1 complex. Our 3.1Å structure reveals, in molecular detail, the major contacts between dynein and Lis1 and between Lis1's β-propellers. Structure-guided mutations in Lis1 and dynein show that these contacts are required for Lis1's ability to form fully active human dynein complexes and to regulate yeast dynein's mechanochemistry and in vivo function. We present a model for the conserved role of Lis1 in regulating dynein from yeast to humans.

scholarly journals Structural basis for cytoplasmic dynein-1 regulation by Lis1

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
John P Gillies ◽  
Janice M Reimer ◽  
Eva P Karasmanis ◽  
Indrajit Lahiri ◽  
Zaw Min Htet ◽  
...  
Keyword(s):  
High Resolution ◽  
Cytoplasmic Dynein ◽  
Motor Domain ◽  
Structural Basis ◽  
Neurodevelopmental Disease ◽  
Molecular Detail ◽  
Microtubule Motor ◽  
High Resolution Structure ◽  
Resolution Structure

The lissencephaly 1 gene, LIS1, is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator known to bind directly to dynein's motor domain, and by doing so alters dynein's mechanochemistry. Lis1 is required for the formation of fully active dynein complexes, which also contain essential cofactors: dynactin and an activating adaptor. Here, we report the first high-resolution structure of the yeast dynein–Lis1 complex. Our 3.1Å structure reveals, in molecular detail, the major contacts between dynein and Lis1 and between Lis1's ß-propellers. Structure-guided mutations in Lis1 and dynein show that these contacts are required for Lis1's ability to form fully active human dynein complexes and to regulate yeast dynein's mechanochemistry and in vivo function.

The high-resolution structure of DNA-binding protein HU from Bacillus stearothermophilus

1999 ◽  
Vol 55 (4) ◽  
pp. 801-809 ◽  
Author(s):  
Stephen W. White ◽  
Keith S. Wilson ◽  
Krzysztof Appelt ◽  
Isao Tanaka
Keyword(s):  
High Resolution ◽  
Protein Interactions ◽  
Bacillus Stearothermophilus ◽  
Helical Structure ◽  
Structural Basis ◽  
Hydrophobic Core ◽  
Salt Bridges ◽  
Medium Resolution ◽  
High Resolution Structure ◽  
Resolution Structure

Protein HU is a ubiquitous prokaryotic protein which controls the architecture of genomic DNA. It binds DNA non-specifically and promotes the bending and supercoiling of the double helical structure. HU is involved in many DNA-associated cellular processes, including replication, transcription and the packaging of DNA into chromosome-like structures. Originally determined at medium resolution, the crystal structure of HU has now been refined at 2.0 Å resolution. The high-resolution structure shows that the dimeric molecule is essentially a compact platform for two flexible and basic arms which wrap around the DNA molecule. To maximize the protein's stability, non-secondary structural regions are reduced to a minimum, there is an extensive aromatic hydrophobic core and several salt bridges and hydrogen-bonded water molecules knit together crucial regions. Based on the original medium-resolution structure of HU, several proposals were made concerning the structural basis of HU's ability to bind, bend and supercoil DNA. Each of these proposals is fully supported by the high-resolution structure. Most notably, the surfaces of the molecule which appear to mediate protein–DNA and protein–protein interactions have the ideal shapes and physicochemical properties to perform these functions.

What we have learned from ribosome structures

2008 ◽  
Vol 36 (4) ◽  
pp. 567-574 ◽  
Author(s):  
V. Ramakrishnan
Keyword(s):  
High Resolution ◽  
Ribosomal Subunit ◽  
Ribosomal Subunits ◽  
30S Subunit ◽  
High Resolution Structure ◽  
70S Ribosome ◽  
Year 2000 ◽  
Resolution Structure

The determination of the high-resolution structures of ribosomal subunits in the year 2000 and of the entire ribosome a few years later are revolutionizing our understanding of the role of the ribosome in translation. In the present article, I summarize the main contributions from our laboratory to this worldwide effort. These include the determination of the structure of the 30S ribosomal subunit and its complexes with antibiotics, the role of the 30S subunit in decoding, and the high-resolution structure of the entire 70S ribosome complexed with mRNA and tRNA.

scholarly journals Insights into LIS1 function in cargo-adapter-mediated dynein activation in vivo

2019 ◽  
Author(s):  
Rongde Qiu ◽  
Jun Zhang ◽  
Xin Xiang
Keyword(s):  
Aspergillus Nidulans ◽  
Mechanism Of Action ◽  
Developmental Disorder ◽  
Model Organism ◽  
Cytoplasmic Dynein ◽  
Significant Extent ◽  
Experimental Systems ◽  
Microtubule Motor

AbstractDeficiency of the LIS1 protein causes lissencephaly, a brain developmental disorder. Although LIS1 binds the microtubule motor cytoplasmic dynein and has been linked to dynein function in many experimental systems, its mechanism of action remains unclear. Here we revealed the function of LIS1 in cargo-adapter-mediated dynein activation in the model organism Aspergillus nidulans. Specifically, we found that overexpressed cargo adapter HookA (Hook in A. nidulans) missing its cargo-binding domain (ΔC-HookA) causes dynein and its regulator dynactin to relocate from the microtubule plus ends to the minus ends, and this dramatic relocation requires LIS1 and its binding protein NudE. Astonishingly, the requirement for LIS1 or NudE can be bypassed to a significant extent by specific mutations that open the auto-inhibited “phi-dynein” in which the motor domains of the dynein dimer are held close together. Our results suggest a novel mechanism of LIS1 action: it promotes the switch of dynein from the auto-inhibited state to an open state to facilitate dynein activation.SummaryThis study reveals the role of Lissencephaly 1 (LIS1) in cargo-adapter-mediated dynein activation. Furthermore, it discovers a novel mechanism of LIS1 action involving a switch of dynein from an auto-inhibited state to an active state.

scholarly journals High-resolution structure of podovirus tail adaptor suggests repositioning of an octad motif that mediates the sequential tail assembly

2017 ◽  
Vol 115 (2) ◽  
pp. 313-318 ◽  
Author(s):  
Lingfei Liang ◽  
Haiyan Zhao ◽  
Bowen An ◽  
Liang Tang
Keyword(s):  
High Resolution ◽  
Adaptor Protein ◽  
Underlying Mechanism ◽  
Life Cycles ◽  
Sequence Motif ◽  
Ring Model ◽  
High Resolution Structure ◽  
Two Sides ◽  
Resolution Structure

The sophisticated tail structures of DNA bacteriophages play essential roles in life cycles. Podoviruses P22 and Sf6 have short tails consisting of multiple proteins, among which is a tail adaptor protein that connects the portal protein to the other tail proteins. Assembly of the tail has been shown to occur in a sequential manner to ensure proper molecular interactions, but the underlying mechanism remains to be understood. Here, we report the high-resolution structure of the tail adaptor protein gp7 from phage Sf6. The structure exhibits distinct distribution of opposite charges on two sides of the molecule. A gp7 dodecameric ring model shows an entirely negatively charged surface, suggesting that the assembly of the dodecamer occurs through head-to-tail interactions of the bipolar monomers. The N-terminal helix-loop structure undergoes rearrangement compared with that of the P22 homolog complexed with the portal, which is achieved by repositioning of two consecutive repeats of a conserved octad sequence motif. We propose that the conformation of the N-terminal helix-loop observed in the Sf6-gp7 and P22 portal:gp4 complex represents the pre- and postassembly state, respectively. Such motif repositioning may serve as a conformational switch that creates the docking site for the tail nozzle only after the assembly of adaptor protein to the portal. In addition, the C-terminal portion of gp7 shows conformational flexibility, indicating an induced fit on binding to the portal. These results provide insight into the mechanistic role of the adaptor protein in mediating the sequential assembly of the phage tail.

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