Plectin is an intermediate filament-binding protein that acts as a cross-linking elementin the cytoskeleton. Sequence analysis reveals that plectin is dumbbell shaped and contains a long central α-helical coiled-coil rod flanked by globular domains. Plectinhas six C-terminal repeats that exhibit a tandemly repeated amino acid sequence motif that is characteristic of intermediate filament-associated proteins, such as BPAG1 and desmoplakin. Plectin associates with the sarcolemma, nuclear membrane, and intermyofibrillar network in muscle and with hemidesmosmes in skin. These localizations may be a result of plectin binding to a variety of cytoskeletal proteins including laminin B, microtubule-associated proteins, and α-spectrin. In addition, plectin interacts with G-actin in a PIP2-dependent manner and with actin stress fibers viaits N-terminal actin-binding domain. Patients with epidermolysis bullosa simplex, adisease that results in structural and functional abnormalities in muscle and skin, have no plectin expression in muscle tissues and deficient plectin levels in skin. Thus, plectin cytoskeletal association may be critical for the structural integrity of muscle and skin.