Nonlinear mechanics of lamin filaments and the meshwork topology build an emergent nuclear lamina

Abstract

The nuclear laminaa meshwork of intermediate filaments termed laminsfunctions as a mechanotransduction interface between the extracellular matrix and the nucleus via the cytoskeleton. Although lamins are primarily responsible for the mechanical stability of the nucleus in multicellular organisms, in situ characterization of lamin filaments under tension has remained elusive. Here, we apply an integrative approach combining atomic force microscopy, cryoelectron tomography, network analysis, and molecular dynamics simulations to directly measure the mechanical response of single lamin filaments in its threedimensional meshwork. Endogenous lamin filaments portray non-Hookean behaviorthey deform reversibly under a force of 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 the meshwork topology follows 'small world' properties. Our results suggest that the lamin filaments arrange to form a robust, emergent meshwork that dictates the mechanical properties of individual lamin filaments. The combined approach provides quantitative insights into the structure-function organization of lamins in situ, and implies a role of meshwork topology in laminopathies.

Characterizing the degeneration of nuclear membrane and mitochondria of adipose‐derived mesenchymal stem cells from patients with type II diabetes

“…In this study, the nuclear membrane of T2DM-ADSCs was shown to be deformed and swollen. In the cellular nucleus, the intermediate filament protein, lamin, forms a network structure called lamina, 23 which connects the nuclear membrane with chromatin. The laminae stabilize the nuclear structure and are involved in chromatin organization, gene transcription, and DNA replication.…”

Structural heterogeneity of cellular K5/K14 filaments as revealed by cryo-electron microscopy

“…When compared to microtubules or actin filaments, which have persistence lengths of ~7 -22 µm and several mm, respectively, keratin filaments are much more flexible (60). Their long α-helical building blocks allow them to accommodate high bending, similar to nuclear lamins (40,61). Previous studies showed that the persistence length of K8/K18 filaments can vary significantly between 300 -650 nm depending on the method used (46,62,63).…”

Nuclear lamin isoforms differentially contribute to LINC complex-dependent nucleocytoskeletal coupling and whole cell mechanics

“…Lamins are proposed to regulate nuclear mechanics not only through their non-linear mechanical properties as intermediate filament polymers but also through their influence on the organizational state of chromatin (e.g., euchromatin vs. heterochromatin) (26)(27)(28)(29). However, the individual contribution of each lamin isoform to nuclear stiffness is incompletely understood.…”