Accessorizing and anchoring the LINC complex for multifunctionality

Abstract

The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of outer and inner nuclear membrane Klarsicht, ANC-1, and Syne homology (KASH) and Sad1 and UNC-84 (SUN) proteins, respectively, connects the nucleus to cytoskeletal filaments and performs diverse functions including nuclear positioning, mechanotransduction, and meiotic chromosome movements. Recent studies have shed light on the source of this diversity by identifying factors associated with the complex that endow specific functions as well as those that differentially anchor the complex within the nucleus. Additional diversity may be provided by accessory factors that reorganize the complex into higher-ordered arrays. As core components of the LINC complex are associated with several diseases, understanding the role of accessory and anchoring proteins could provide insights into pathogenic mechanisms.

Figure 1.

The LINC complex bridges the cytoskeleton and nucleoskeleton. The LINC complex is composed of KASH proteins in the outer nuclear membrane and SUN proteins in the inner nuclear membrane. The lumenal region of SUN proteins forms a triple helical coiled-coil, allowing trimerization of their SUN domains. The hydrophobic groove between neighboring SUN domains is required for the KASH peptide to bind, and this interaction is further strengthened by a KASH-lid of the SUN domain (see text). The cytoplasmic extensions of KASH proteins vary in size and interact with different cytoskeletal elements. Mammalian KASH proteins typically contain several SRs (see text). The nucleoplasmic domains of SUN proteins anchor the LINC complex to the nucleoskeleton, through its interaction with nuclear lamina, as well as chromosome-binding proteins and probably other anchoring proteins (see Fig. 3). INM, inner nuclear membrane; ONM, outer nuclear membrane.

Figure 2.

Domain structures of KASH proteins and their interacting proteins. Schematics are shown summarizing findings in mammals and C. elegans where the most information is available. Lines under KASH proteins indicate binding regions. “Unmapped” refers to proteins whose sites of interaction have not yet been identified. Giant KASH proteins (e.g., nesprin-1G, nesprin-2G, and ANC-1) contain CH domains that bind to F-actin, microtubule motors, and signaling proteins. The small isoforms typically interact with microtubule motors and/or their regulators. Interacting proteins in blue are characterized in isoforms lacking the KASH domain. Note that two KASH proteins, mammalian LRMP and C. elegans KDP-1, were omitted because of the lack of known interacting proteins.

Figure 3.

Anchoring the LINC complex. Mammalian SUN proteins are anchored to the inner nuclear membrane through at least three different mechanisms. (A) The nucleoplasmic tail of SUN2 binds to lamin A and anchors the LINC complex to the nuclear lamina in somatic cells. Samp1 and emerin are required to strengthen this anchorage during nuclear movement, presumably to resist the high mechanical force. For clarity, nesprin-2G is shown as a shorter protein without all of its 56 SRs. INM, inner nuclear membrane; ONM, outer nuclear membrane. (B) The nucleoplasmic tail of SUN1 binds TERB1 and anchors the LINC complex to chromosomes through telomere binding proteins (TRF1 and cohesion) in meiotic cells. Lamin C2 also associates with this complex, probably through SUN1 binding. (C) Nucleoplasmic tails of SUN proteins shown binding to nuclear pores (SUN1) and a hypothetical protein as possible alternative anchors for the LINC complex in somatic cells. As described in the text, the localization of SUN1 and SUN2 in the nuclear membrane is only slightly affected in somatic cells lacking all lamins, which indicates the presence of additional anchoring factors.