Abstract
The nuclear lamina—a meshwork of intermediate filaments termed lamins—is primarily responsible for the mechanical stability of the nucleus in multicellular organisms. However, structural-mechanical characterization of lamin filaments assembled in situ remains elusive. Here, we apply an integrative approach combining atomic force microscopy, cryo-electron tomography, network analysis, and molecular dynamics simulations to directly measure the mechanical response of single lamin filaments in three-dimensional meshwork. Endogenous lamin filaments portray non-Hookean behavior – they deform reversibly at a few hundred picoNewtons and stiffen at nanoNewton forces. The filaments are extensible, strong and tough similar to natural silk and superior to the synthetic polymer Kevlar®. Graph theory analysis shows that the lamin meshwork is not a random arrangement of filaments but exhibits small-world properties. Our results suggest that lamin filaments arrange to form an emergent meshwork whose topology dictates the mechanical properties of individual filaments. The quantitative insights imply a role of meshwork topology in laminopathies.
Highlights
The nuclear lamina—a meshwork of intermediate filaments termed lamins—is primarily responsible for the mechanical stability of the nucleus in multicellular organisms
Owing to its sheer size (~400 μm diameter) and a condensed chromatin structure that is not associated with the lamina[5], we utilized the X. laevis oocyte nucleus for atomic force microscope (AFM) measurements of lamin filaments assembled in situ
Assembled meshwork of single B-type lamin filaments has been visualized by electron microscopy in spread nuclear envelope (NE) of the X. laevis oocytes[7,37,38]
Summary
The nuclear lamina—a meshwork of intermediate filaments termed lamins—is primarily responsible for the mechanical stability of the nucleus in multicellular organisms. We apply an integrative approach combining atomic force microscopy, cryo-electron tomography, network analysis, and molecular dynamics simulations to directly measure the mechanical response of single lamin filaments in three-dimensional meshwork. Direct mechanical interrogation of native lamin filaments remains a pertinent goal towards understanding the mechanical properties of the lamina and the nucleus in health and disease[18,29,30,31]. In this work, using a combined mechanical, structural, and simulation approach, we characterize in situ assembled lamin filaments by applying point loads and measure their deformation and apparent failure in the native meshwork (Fig. 1). The in vitro mechanical behavior of lamin filaments is recapitulated in silico by molecular dynamics (MD) simulations of single filaments in a meshwork model[32] derived from cryo-electron tomography (cryo-ET) of the nuclear lamina. The study provides a general understanding of lamin filaments and nuclear lamina mechanics relevant to laminopathies
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