Structural insights into LINC complexes

Abstract

Communication between nucleus and cytoplasm extends past molecular exchange and critically includes mechanical wiring. Cytoskeleton and nucleoskeleton are connected via molecular tethers that span the nuclear envelope. Sad1, UNC84 (SUN)-domain proteins spanning the inner nuclear membrane and Klarsicht, ANC-1 and SYNE/Nesprin-1 and -2 Homology (KASH)-peptide bearing proteins residing in the outer nuclear membrane directly bind and constitute the core of the LInkers of Nucleoskeleton and Cytoskeleton (LINC) complex. These connections appear critical for a growing number of biological processes and aberrations are implicated in a host of diverse diseases, including muscular dystrophies, cardiomyopathies, and premature aging. We discuss recent developments in this vibrant research area, particularly in context of first structural insights into LINC complexes reported in the past year.

Figure 1

Multiple sequence alignment of KASH peptides from highly diverged eukaryotes, including vertebrates, various metazoans, yeast, and plants. The numbers above the sequence mark residues in human Nesprin2/SYNE2 important for SUN binding according to [17].

Figure 2

A) Overview of a human SUN2 protomer isolated from its Nesprin-2 binding partners in the trimeric SUN-KASH complex [17]. The protein is organized around a compact β-sandwich core, decorated with features important for function (labeled). Bound cation depicted as a green sphere. B) View from the ONM facing the bottom of the trimeric SUN2 arrangement (blue colors) with three individual KASH peptides (orange) bound. C) Side view of the SUN2-KASH2 complex. It is easy to recognize how deeply the three KASH peptides are buried in clefts formed between neighboring SUN2 protomers. D) Explosion view of the KASH peptide interacting with neighboring SUN domains in the SUN2 trimer. Areas on the SUN domains in close contact with the KASH peptide are highlighted in orange. Note the L-shaped, extended conformation of the bound KASH peptide. Important residues for SUN interaction are labeled in the zoomed, stick representation of KASH2.

Figure 3

Various SUN proteins exhibit predicted perinuclear α-helical coiled-coil domains of various length. If these elements are modeled as trimeric coiled-coils, currently the most likely scenario, spacing between INM and ONM would vary dependent on the employed SUN protein.