Lamin-binding Proteins

Abstract

A- and B-type lamins are the major intermediate filaments of the nucleus. Lamins engage in a plethora of stable and transient interactions, near the inner nuclear membrane and throughout the nucleus. Lamin-binding proteins serve an amazingly diverse range of functions. Numerous inner-membrane proteins help anchor lamin filaments to the nuclear envelope, serving as part of the nuclear "lamina" network that is essential for nuclear architecture and integrity. Certain lamin-binding proteins of the inner membrane bind partners in the outer membrane and mechanically link lamins to the cytoskeleton. Inside the nucleus, lamin-binding proteins appear to serve as the "adaptors" by which the lamina organizes chromatin, influences gene expression and epigenetic regulation, and modulates signaling pathways. Transient interactions of lamins with key components of the transcription and replication machinery may provide an additional level of regulation or support to these essential events.

Figure 1.

Overview of known roles for lamin-binding proteins. Many lamin-binding proteins located in the INM, on chromatin, and in the nucleoplasm are thought to have mechanical and structural roles, such as reinforcing the nucleoskeleton, interlinking the nucleoskeleton and cytoskeleton, anchoring NPCs, and tethering chromatin to the nuclear envelope. Others regulate signaling or transcription. Many lamin-binding proteins require lamins for their correct localization, whereas others regulate or facilitate lamin assembly.

Figure 2.

LEM-domain proteins organize chromatin and regulate signaling and transcription. Domain organizations of characterized LEM proteins; the LEM motif confers direct binding to barrier to autointegration factor (BAF). All LEM proteins can bind A- and/or B-type lamins. Some, including human (h-)emerin, C. elegans (Ce-) emerin, D. melanogaster (Dm-) bocksbeutel α, and Dm-Otefin, have one transmembrane (TM) domain. LAP2 proteins, expressed only in vertebrates, also have a DNA-binding “LEM-like” domain. Others (e.g., hLem2, Ce-Lem2, hMAN1, and Dm-MAN1) have two TM domains and a carboxy-terminal Winged Helix domain that binds DNA. Some, including hLAP2α (shown) and three uncharacterized LEM proteins (not shown), have no TM domain. LEM proteins have additional functional domains; e.g., LAP2β partners include replication protein HA95 and HDAC3; LAP2β recruits HDAC3 to the NE and contributes to epigenetic regulation. Emerin binds many transcription factors including GCL, Lmo7, Btf, and β-catenin. GCL also binds hLAP2β and hMAN1, suggesting functional overlap. MAN1 is unique in binding regulatory Smads, and inhibits BMP and TGF-β signaling.

Figure 3.

SUN- and KASH-domain proteins interact in the NE lumen to form LINC (Links Nucleoskeleton and Cytoskeleton) complexes. SUN-domain proteins span the INM and dimerize; each nucleoplasmic domain binds lamins and each SUN-domain in the NE lumen binds the KASH domain of an ONM-embedded KASH protein, which binds actin, centrosomes/microtubules, or plectin/intermediate filaments in the cytoplasm. Only one KASH domain partner of a SUN dimer is depicted. SUN proteins also bind, potentially via Him-8, the pairing centers of meiotic chromosomes. Many additional nesprin isoforms reside elsewhere, including the INM; e.g., human nesprins-1α and -2β in the INM bind lamins and emerin (not shown).