Nuclear lamins: Structure and function in mechanobiology

Abstract

Nuclear lamins are type V intermediate filament proteins that polymerize into complex filamentous meshworks at the nuclear periphery and in less structured forms throughout the nucleoplasm. Lamins interact with a wide range of nuclear proteins and are involved in numerous nuclear and cellular functions. Within the nucleus, they play roles in chromatin organization and gene regulation, nuclear shape, size, and mechanics, and the organization and anchorage of nuclear pore complexes. At the whole cell level, they are involved in the organization of the cytoskeleton, cell motility, and mechanotransduction. The expression of different lamin isoforms has been associated with developmental progression, differentiation, and tissue-specific functions. Mutations in lamins and their binding proteins result in over 15 distinct human diseases, referred to as laminopathies. The laminopathies include muscular (e.g., Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy), neurological (e.g., microcephaly), and metabolic (e.g., familial partial lipodystrophy) disorders as well as premature aging diseases (e.g., Hutchinson-Gilford Progeria and Werner syndromes). How lamins contribute to the etiology of laminopathies is still unknown. In this review article, we summarize major recent findings on the structure, organization, and multiple functions of lamins in nuclear and more global cellular processes.

FIG. 1.

The organization of the nuclear lamins. The INM and ONM seal the NE leaving NPCs as sole openings between the nucleoplasm and cytoplasm. The NL is a meshwork formed by A- and B-type lamins and their associated proteins adjacent to the INM. The A- and B-type lamins at the NL interact with the peripheral heterochromatin lamina associated domains (LADs) and regulate their organization via direct interaction or indirect mechanisms that are mediated by lamin associated proteins. The A- and B-type lamins further mobilize to the nucleoplasm to engage with the active euchromatin domains.

FIG. 2.

The general structure of lamin intermediate filament proteins. Nuclear lamins consist of the N-terminal (head) domain; the central rod domain, which includes four α-helical domains (coils 1A, 1B, 2A, and 2B) and three flexible linker regions (L1, L12, and L2); and the C-terminal (tail) domain that includes the nuclear localization signal (NLS), the globular immunoglobulin (Ig) fold, and a CaaX motif.

FIG. 3.

The structure and assembly of nuclear lamins. (a) The structural domains of LA/C, LB1, and LB2 in mammals, Ce-lamin in C. elegans, and Lamin-LIII in X. laevis. (b) Cryo-ET tomogram of bacterially expressed and purified C. elegans demonstrate that lamins assemble into ∼8 nm thick filaments in low ionic strength buffers. (c) Cryo-ET of human lamin A assembled into paracrystaline structures in vitro. (d) Lamin filament meshwork is exposed via a cryo-ET slice of a MEF nucleus treated with nuclease. (e) A cryo-ET of native nuclear lamins in MEF nucleus reveals chromatin (arrows) and lamin filaments (arrow heads). (f) 2D averaging shows a 3.5 nm think rod domain (blue arrowhead) with globular Ig-folds (red arrowheads) with a repeat sequence of 20 nm. Reprinted with permission from R. Tenga and O. Medalia, “Structure and unique mechanical aspects of nuclear lamin filaments,” Curr. Opin. Struct. Biol. 64, 152–159 (2020). Copyright 2020 Elsevier.

FIG. 4.

Nuclear lamins facilitate nucleocytoskeletal connections. The LINC complex spans the NE through interplay between its INM SUN and ONM nesprin domains. The nesprin (nesprin-1, -2, -3, and -4) domains of LINC complexes interact with the F-actin, microtubule, and intermediate filament cytoskeletal systems in the cytoplasm via direct binding or adaptor proteins while the SUN (SUN1 and SUN2) domains engage with the A- and B-type lamins as well as lamin associated proteins. The A- and B-type lamins stabilize the SUN, and by extension, nesprin domains of the LINC complexes and their loss are associated with increased mobility of these proteins at the NE, which in turn disrupts cytoskeletal organization within the cell. Reproduced with permission from M. Maurer and J. Lammerding, “The driving force: Nuclear mechanotransduction in cellular function, fate, and disease,” Annu. Rev. Biomed. Eng. 21, 443–468 (2019). Copyright 2021 Annual Reviews.

FIG. 5.

The in situ mechanical characterization of lamin filaments. (a) Schematic illustration of the experimental setup for characterization of lamin filaments in nuclei isolated from X. laevis oocytes; the nuclei were attached to poly-L-Lysine-coated dishes and then dissected for chromatin digestion and AFM imaging and force spectroscopy experiments. (b) AFM images of the lamina from the nucleoplasmic side showing lamin filaments interconnected with NPCs; scale bar is 100 nm. (c) Typical force-extension curve for nonlinear behavior of a lamin filament. When subjected to mechanical compression, a single lamin filament shows a low force regime with a yield point (the point of transition from a reversible elastic deformation to an irreversible plastic one) from which it undergoes a steep transition to a high force regime followed by failure of the filament. The different force regimes of the filament are assigned to the changes in the lamin α-helical coiled-coils, in which low force regimes (I and II) represent unfolding of the coiled-coil structure, the high force regime (III) denotes the transition from the α-helix to β-sheets, and filament failure (IV) represents the failure of the β-sheets. (d) Schematic model for the lamin filaments response to external forces in situ. Reproduced with permission from K. T. Sapra and O. Medalia, “Bend, push, stretch: Remarkable structure and mechanics of single intermediate filaments and meshworks,” Cells 10, 1960 (2021). Copyright 2021 Author(s), licensed under a Creative Commons Attribution (CC BY) license.