Biology subjects

Chaaban, S.

Publications and source records attributed to Chaaban, S..

5 recordsLinked to original sources

bioRxiv2026

Structural basis of dynein interaction with diverse activating adaptors

Cargo-specific activating adaptors enable dynein to assemble with dynactin into processive supercomplexes. Adaptors share a coiled-coil architecture, but are highly diverse in sequence and structure, raising the question of how they converge on a common activation mechanism. To address this, we determined near atomic cryo-EM structures of dynein-dynactin assembled with five adaptors: RAB11FIP3, NIN, TRAK1, BICD2 and HOOK3. Despite their heterogeneity, all complexes contain adaptor coiled coils which bridge two dynein dimers to the dynactin filament. Adaptors are defined by an N-terminal interaction at the HBS1 with the dynein heavy chain, additional contacts along the dynein-dynactin groove, and C-terminal binding to the dynactin pointed end. However, we also found distinct sequence features, coiled-coil breaks and pointed-end interfaces that tune complex stoichiometry and stability. Our results define shared principles of dynein activation while revealing unexpected plasticity in how adaptors recognise and organise the dynein-dynactin machinery.

molecular biology↗

bioRxiv2024

Evolutionarily conserved principles of ESCRT-III-mediated membrane remodelling revealed by a two-subunit Asgard archaeal system

ESCRT-III proteins assemble into composite polymers that undergo stepwise changes in composition and structure to deform membranes across the tree of life. Here, using a phylogenetic analysis we demonstrate that the two ESCRT-III proteins present in our closest archaeal relatives are evolutionarily related to B-type and A-type eukaryotic paralogues, which initiate and execute membrane remodelling, respectively. This deep homology is reflected in ESCRT-III structure and function as demonstrated by the fact that ESCRT-IIIB assembles into parallel arrays on planar membranes to initiate membrane deformation, and is required to recruit ESCRT-IIIA to generate composite polymers. ESCRT-IIIA homopolymers can then remodel membranes into tubes, as a likely prelude to scission. Taken together, this analysis reveals a set of conserved principles governing ESCRT-III-dependent membrane remodelling that first emerged with the evolution of a two-component ESCRT-III system in the Asgard archaea, and which continue to underlie complex multi-component, ESCRT-III-dependent membrane remodelling in eukaryotes.

evolutionary biology↗

bioRxiv2023

A force-sensitive mutation reveals a spindle assembly checkpoint-independent role for dynein in anaphase progression

The cytoplasmic dynein-1 (dynein) motor organizes cells by shaping microtubule networks and moving a large variety of cargoes along them. However, dyneins diverse roles complicate in vivo studies of its functions significantly. To address this issue, we have used gene editing to generate a series of missense mutations in Drosophila Dynein heavy chain (Dhc). We find that mutations associated with human neurological disease cause a range of defects in larval and adult flies, including impaired cargo trafficking in neurons. We also describe a novel mutation in the microtubule-binding domain (MTBD) of Dhc that, remarkably, causes metaphase arrest of mitotic spindles in the embryo but does not impair other dynein-dependent processes. We demonstrate that the mitotic arrest is independent of dyneins well-established roles in silencing the spindle assembly checkpoint. In vitro reconstitution and optical trapping assays reveal that the mutation only impairs the performance of dynein under load. In silico all-atom molecular dynamics simulations show that this effect correlates with increased flexibility of the MTBD, as well as an altered orientation of the stalk domain, with respect to the microtubule. Collectively, our data point to a novel role of dynein in anaphase progression that depends on the motor operating in a specific load regime. More broadly, our work illustrates how cytoskeletal transport processes can be dissected in vivo by manipulating mechanical properties of motors.

cell biology↗

bioRxiv2022

Structure of dynein-dynactin on microtubules shows tandem recruitment of cargo adaptors

Cytoplasmic dynein is a microtubule motor that is activated by its cofactor dynactin and a coiled-coil cargo adaptor. There is currently limited structural information on how the resulting complex interacts with microtubules and how adaptors are recruited. Here, we develop a cryo-EM processing pipeline to solve the high-resolution structure of dynein-dynactin and the adaptor BICDR1 bound to microtubules. This reveals the asymmetric interactions between neighbouring dynein motor domains and how it relates to their motile behaviour. We find unexpectedly that two adaptors occupy the complex. Both adaptors make similar interactions with the dyneins but diverge in their contacts with each other and dynactin. Our structure has implications for the stability and stoichiometry of motor recruitment by cargos.

molecular biology↗

bioRxiv2019

Crystal structure of human PACRG in complex with MEIG1

In human, the Parkin Co-Regulated Gene (PACRG) shares a bidirectional promoter with Parkin, a gene involved in Parkinsons disease, mitochondrial quality control and inflammation. The PACRG protein is essential to the formation of the inner junction between doublet microtubules of the axoneme, a structure found in flagella and cilia. PACRG interacts with tubulin as well as the meiosis expressed gene 1 (MEIG1) protein, which is essential for spermiogenesis in mice. However, the 3D structure of human PACRG is unknown. Here, we report the crystal structure of the C-terminal domain of human PACRG in complex with MEIG1 at 2.1 [A] resolution. PACRG adopts an -helical structure with a loop insertion that mediates a conserved network of interactions with MEIG1. Using the cryo-electron tomography structure of the axonemal doublet microtubule from the flagellated protozoan Chlamydomonas reinhardtii, we generate a model of a mammalian microtubule doublet inner junction, which reveals how PACRG interacts with tubulin subunits in both the A- and B-tubules. Furthermore, the model shows that MEIG1 interacts with {beta}-tubulin on the outer surface of the B-tubule, facing towards the central pair of the axoneme. We also model the PACRG-like protein (PACRGL), a homolog of PACRG with potential roles in microtubule remodelling and axonemal inner junction formation. Finally, we explore the evolution of the PACRG and Parkin head-to-head gene structure and analyze the tissue distribution of their transcripts. Our work establishes a framework to assess the function of the PACRG family of proteins and its adaptor proteins in the function of motile and non-motile cilia.

cell biology↗