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bioRxiv · 10.1101/2024.10.21.619497

Exploring Nuclear Lamina Structure and Lamin Dissociation in Progeria through Polymer Modeling

Hameed, H. A.·Paturej, J.·Erbas, A.
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Abstract

One of the key structural proteins in the eukaryotic cell nucleus is lamin. Lamins can assemble into a two-dimensional protein meshwork at the nuclear periphery, referred to as the nuclear lamina, which provides rigidity and shape to the nucleus. Mutations in lamin proteins that affect the structure of the nuclear lamina underlie laminopathic diseases, including Hutchinson-Gilford Progeria Syndrome (HGPS). Experiments have shown that, compared to healthy cells, lamin supramolecular structures (e.g., protofilaments) assemble into a thicker lamina structure in HGPS, where lamins form highly stable nematic microdomains at the nuclear periphery, reminiscent of liquid crystals. This significantly alters the morphological and mechanical properties of the nucleus. In this study, we investigate the aggregation of lamin fibrous structures and their dissociation kinetics from the nuclear periphery by modeling them as coarse-grained, rod-like polymer chains confined in a rigid spherical shell. Our model recapitulates the formation of multidirectional nematic domains at the nuclear surface and the reduced lamin dissociation observed in HGPS nuclei by adjusting lamin concentration, lamin-lamin (specifically head-tail), and lamin-shell association strengths. While nematic phase formation requires relatively strong lamin-shell affinity under any non-vanishing inter-lamin attraction, the thickness of this layer is primarily controlled by head-tail association strength in the model. Furthermore, the dissociation kinetics of lamin chains from the chain aggregates at the periphery (lamina) exhibits a concentration-dependent dissociation (facilitated dissociation) pattern governed by weak lamin-lamin interactions, reminiscent of healthy nuclei. Overall, our calculations demonstrate how an interplay between molecular interactions altered by mutations and lamin concentration can lead to an abnormal nuclear lamina in laminopathic diseases.

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Hameed, H. A., Paturej, J., Erbas, A.. 2024-10-24. Exploring Nuclear Lamina Structure and Lamin Dissociation in Progeria through Polymer Modeling. https://doi.org/10.1101/2024.10.21.619497

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