Plectin, the most versatile cytolinker identified to date, has essential functions in maintaining the mechanical integrity of skin, skeletal muscle and heart, as indicated by analyses of plectin-deficient mice and humans. Expression of plectin in a vast variety of tissues and cell types, combined with a large number of different binding partners identified at the molecular level, calls for complex mechanisms regulating gene transcription and expression of the protein. To investigate these mechanisms, we analyzed the transcript diversity and genomic organization of the murine plectin gene and found a remarkable complexity of its 5'-end structure. An unusually high number of 14 alternatively spliced exons, 11 of them directly splicing into plectin exon 2, were identified. Analysis of their tissue distribution revealed that expression of a few of them is restricted to tissues such as brain, or skeletal muscle and heart. In addition, we found two short exons tissue-specifically spliced into a highly conserved set of exons encoding the N-terminal actin binding domain (ABD), common to plectin and the superfamily of spectrin/dystrophin-type actin binding proteins. Using recombinant proteins we show that a novel ABD version contained in the muscle-specific isoform of plectin exhibits significantly higher actin binding activity than other splice forms. This fine tuning mechanism based on alternative splicing is likely to optimize the proposed biological role of plectin as a cytolinker opposing intense mechanical forces in tissues like striated muscle.

Hemidesmosomes are multiprotein complexes that facilitate the stable adhesion of basal epithelial cells to the underlying basement membrane. The mechanical stability of hemidesmosomes relies on multiple interactions of a few protein components that form a membrane-embedded tightly-ordered complex. The core of this complex is provided by integrin α6β4 and P1a, an isoform of the cytoskeletal linker protein plectin that is specifically associated with hemidesmosomes. Integrin α6β4 binds to the extracellular matrix protein laminin-332, whereas P1a forms a bridge to the cytoplasmic keratin intermediate filament network. Other important components are BPAG1e, the epithelial isoform of bullous pemphigoid antigen 1, BPAG2, a collagen-type transmembrane protein and CD151. Inherited or acquired diseases in which essential components of the hemidesmosome are missing or structurally altered result in tissue fragility and blistering. Modulation of hemidesmosome function is of crucial importance for a variety of biological processes, such as terminal differentiation of basal keratinocytes and keratinocyte migration during wound healing and carcinoma invasion. Here, we review the molecular characteristics of the proteins that make up the hemidesmosome core structure and summarize the current knowledge about how their assembly and turnover are regulated by transcriptional and post-translational mechanisms.

Plectin is a large, 500-kDa, intermediate filament (IF)-associated protein. It acts as a cytoskeletal crosslinker and signaling scaffold, affecting mechanical as well as dynamic properties of the cytoskeleton. As a member of the plakin family of cytolinker proteins, plectin has a multidomain structure that is responsible for its vast binding portfolio. It not only binds to all types of IFs, actin filaments and microtubules, but also to transmembrane receptors, proteins of the subplasma membrane protein skeleton, components of the nuclear envelope, and several kinases with known roles in migration, proliferation, and energy metabolism of cells. Due to alternative splicing, plectin is expressed as various isoforms with differing N-terminal heads that dictate their differential subcellular targeting. Through specific interactions with other proteins at their target sites and their ability to bind to all types of IFs, plectin molecules provide strategically located IF anchorage sites within the cytoplasm of cells. In this review, we will present an overview of the structural features and functional properties of plectin and discuss recent progress in defining the role of its isoforms in stress-prone tissues and the implicated diseases, with focus on skin, skeletal muscle, and Schwann cells of peripheral nerve.