Lamin-binding Proteins

Abstract

The eukaryotic cell nucleus is a complex membrane-bounded organelle that houses, organizes, and regulates the genome. The nucleus is structurally organized into functional domains, one of which is the nuclear envelope (NE). The NE has two concentric membranes, named the “inner” and “outer” nuclear membranes (INM and ONM, respectively). These membranes are separated by a 30–50 nm lumen, and fuse to form holes (pores) occupied by nuclear pore complexes (NPCs), which mediate active and passive movement of molecules between the cytoplasm and nucleoplasm (Gruenbaum et al. 2005; Stewart et al. 2007). The NE and its lumen are continuous with the endoplasmic reticulum (ER) and share many ER functions. However, the INM and ONM are also each structurally and functionally unique, because of specific enrichments for distinct integral membrane proteins (Schirmer and Gerace 2005; Schirmer and Foisner 2007). In mammals, the INM in particular appears to be populated by over 50 different membrane proteins, most of which are uncharacterized. Among characterized INM proteins, most can bind directly to A- or B-type lamins, or both.

A- and B-type lamins polymerize to form separate networks of nuclear intermediate filaments that concentrate near the INM in metazoans (Dechat et al. 2008). Many INM proteins are localized by binding directly or indirectly to lamin filaments. This network of filaments and lamin-binding proteins at the INM is known as the “peripheral lamina.” B-type lamins are essential for cell viability and development, whereas A-type lamins arose later in evolution and are nonessential. Lamins are important structurally and as “scaffolds” for many other proteins and complexes in the nucleus.

Lamin filaments are important for the assembly, structure, shape, and mechanical stability of metazoan nuclei. There is also growing evidence that lamins regulate chromatin organization and gene expression, and influence signaling (Gruenbaum et al. 2005; Dechat et al. 2008). These functions involve a full spectrum of biochemical interactions between lamins, chromatin, and a variety of partners, including regulatory proteins responsive to external and intrinsic signals (Fig. 1). The pace of discovering new lamin-binding proteins has nearly overwhelmed our capacity to characterize them. Each new partner has the potential to provide fresh insight into the structure and regulation of the nucleoskeleton and its relationships with the genome. Further motivation for research in this area comes with the discovery that an increasing number of human diseases are linked to defects in lamins or lamin-binding proteins.

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.

ACKNOWLEDGMENTS

Footnotes

REFERENCES