Abstract
Plectin, a high-molecular-weight cytoskeletal linker protein, binds with high affinity to intermediate filaments of all types and connects them to junctional complexes, organelles, and inner membrane systems. In addition, it interacts with actomyosin structures and microtubules. As a multifunctional protein, plectin has been implicated in several multisystemic diseases, the most common of which is epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). A great part of our knowledge about plectin’s functional diversity has been gained through the analysis of a unique collection of transgenic mice that includes a full (null) knockout (KO), several tissue-restricted and isoform-specific KOs, three double KOs, and two knock-in lines. The key molecular features and pathological phenotypes of these mice will be discussed in this review. In summary, the analysis of the different genetic models indicated that a functional plectin is required for the proper function of striated and simple epithelia, cardiac and skeletal muscle, the neuromuscular junction, and the vascular endothelium, recapitulating the symptoms of humans carrying plectin mutations. The plectin-null line showed severe skin and muscle phenotypes reflecting the importance of plectin for hemidesmosome and sarcomere integrity; whereas the ablation of individual isoforms caused a specific phenotype in myofibers, basal keratinocytes, or neurons. Tissue-restricted ablation of plectin rendered the targeted cells less resilient to mechanical stress. Studies based on animal models other than the mouse, such as zebrafish and C. elegans, will be discussed as well.
Highlights
Plectin, a 500 kDa cytoskeletal protein, binds to and interconnects intermediate filaments (IFs) and attaches them to junctional complexes at the cell membrane, different organelles, and inner membrane systems
Most of what is known to date about the biological functions of plectin has been gained through the analysis of a series of different knockout mouse models
The first null knockout line was established in 1997, it took over a dozen other transgenic lines of different types, to gain an understanding of plectin’s functional diversity and disease mechanisms
Summary
A 500 kDa cytoskeletal protein, binds to and interconnects intermediate filaments (IFs) and attaches them to junctional complexes at the cell membrane, different organelles, and inner membrane systems. Belonging to the plakin family of proteins, plectin has a multimodular structure with up to seven functional domains. Its variable N-termini, defined by short isoform-specific peptides, are followed by an actin binding domain (ABD) and a plakin domain. These isoform-specific N-termini are responsible for the differential targeting of plectin to different strategic cellular locations such as the nucleus, mitochondria, the contractile apparatus of muscle cells, hemidesmosomes, focal adhesions, the neuromuscular synapse, and others [6]. The central α-helical domain forms a roughly 200 nm long coiled-coil rod upon dimerization. The. The central α-helical domain forms a roughly 200 nm long coiled-coil rod upon dimerizatCio-tne.rTmhienaCl-dteormmaininalcdonomsisatisnocfosnixsitsatsndofemsixlytaanrrdaenmgelydaprlreacntgined(opr lpelcatiknin()orreppleaaktind)ormepaeinast d(PoRmDasin) sse(pPaRraDtes)d sbeyplairnakteerdrebgyiolninskwerherreegitohnescowreheorfethteheIFc-boirnedoinf gthdeomIFa-ibnin(dIFiBnDg )droemsidaeins. No plectin homolog has been found in Drosophila
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