Emerin, a nuclear envelope (NE) protein within mammalian cells, is a fundamental component of the inner nuclear membrane (INM) [Fernandez et. al., 2022]. It plays a pivotal role in mechanotransduction, a process through which mechanical forces are detected and converted into biochemical signals. This function is intricately connected to emerin's role as a key link between the cytoplasmic membrane, the cytoskeleton, and the nucleoskeleton. Emerin is a key component of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. This complex acts as a bridge, connecting the nuclear lamina inside the nucleoplasm to the cytoskeleton on the cytoplasmic side. The LINC complex has the ability to sense and relay mechanical signals from the cytoplasmic membrane to the cell nucleus, which, consequently, can be perceived by emerin. Emerin can affect gene expression involved in the processes of mechanotransduction. For example, by influencing genes such as $\beta$-catenin and Lmo7, emerin can affect cytoskeletal dynamics and cell shape. Numerous studies have highlighted the significance of emerin's intrinsically disordered region in performing many of its vital functions. This structural flexibility allows emerin to adopt various conformations, form oligomers, and engage with multiple partners at the INM [Fernandez et. al., 2022]. Mutations in emerin or its absence have been correlated with abnormal responses of the nuclear envelope to mechanical stress, ultimately resulting in Emery-Dreifuss muscular dystrophy (EDMD).

A recent study utilizing single-molecule tracking and super-resolution fluorescence microscopy has provided intriguing insights into the steady-state distributions and mobilities of wild-type (WT) and mutated emerin at the INM under various conditions, including mechanical stress [Fernandez et. al., 2022]. In particular, these experiments revealed two distinct distributions of emerin species at the INM, slow and fast diffusers, and that emerin generally forms stable nanodomains of elevated emerin concentrations which are maintained through interactions with emerin and other nuclear binding partners (NBPs) [e.g., SUN1, lamin A/C, barrier-to-autointegration factor (BAF), and nuclear actin]. Mutations of emerin and mechanical stress were found to perturb the distributions of emerin and its oligomerization potential.

The INM spatial pattern of emerin nanodomains of increased concentrations and the distinction between slowly and rapidly diffusing emerin species resembles the properties of molecular domains self-assembled through a Turing mechanism in an activator-inhibitor reaction-diffusion model [Haselwandter, 2011]. In this model, inhibitors, which diffuse rapidly, act to restrain increased molecular concentrations via steric constraints. On the other hand, activators diffuse at a slower pace compared to inhibitors but activate elevated molecular concentrations of both inhibitors and other activators. We show that the self-assembly of stable emerin nanodomains may be attributed to the self-stabilization of slow-diffusing, activating emerin-complexes and fast-diffusing, inhibiting emerin-complexes at the INM, coupled with the steric repulsion of the inhibitors.

We developed a physical model of the self-assembly of emerin nanodomains at the INM based on the Turing mechanism. Our model serves three related purposes: (a) to explain how WT emerin nanodomains form when no force is applied, (b) to predict how WT emerin nanodomain properties change under force application based on experimental data on changes in emerin diffusion under force application, and (c) to trace observed changes in emerin organization in mutated forms of emerin to changes in key reaction or diffusion processes.

Our manuscript is currently in peer review. We've uploaded a copy of our submission to arXiv for previewing [Alas et. al., 2024].