Abstract
Nuclear structure and function are governed by lamins, which are intermediate filaments that mostly consist of α-helices. Different lamin assembly models have been proposed based on low resolution and fragmented structures. However, their assembly mechanisms are still poorly understood at the molecular level. Here, we present the crystal structure of a long human lamin fragment at 3.2 Å resolution that allows the visualization of the features of the full-length protein. The structure shows an anti-parallel arrangement of the two coiled-coil dimers, which is important for the assembly process. We further discover an interaction between the lamin dimers by using chemical cross-linking and mass spectrometry analysis. Based on these two interactions, we propose a molecular mechanism for lamin assembly that is in agreement with a recent model representing the native state and could explain pathological mutations. Our findings also provide the molecular basis for assembly mechanisms of other intermediate filaments.
Highlights
Nuclear structure and function are governed by lamins, which are intermediate filaments that mostly consist of α-helices
A typical lefthanded coiled-coil conformation was found in most of the coil 1a and the N-terminal four-fifths of coil 1b (Supplementary Fig. 1a), in which hydrophobic residues were regularly found at the heptad positions a and d (Fig. 2a and Supplementary Fig. 1b; highlighted in yellow)
The hendecad pattern is composed of 11 amino-acid repeats, where the residues at the a, d, and h positions are involved in the inter-helical hydrophobic interactions (Fig. 2a and Supplementary Fig. 1b; highlighted in magenta)
Summary
Nuclear structure and function are governed by lamins, which are intermediate filaments that mostly consist of α-helices. Different lamin assembly models have been proposed based on low resolution and fragmented structures. Their assembly mechanisms are still poorly understood at the molecular level. The intrinsic structural flexibility and self-aggregative properties of lamin have allowed determination of only low-resolution electron microscopy (EM) structures and crystal structures of short fragments[24,25,26]. To date, their assembly mechanisms at the molecular level are poorly understood[16,26,27,28]. This study provides a structural basis for how the lamin filament is assembled with two interactions, giving insights into the assembly mechanisms of other IFs
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