Plectin is a giant
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
found in nearly all
mammalian
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
cells which acts as a link between the three main components of the
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...
:
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
microfilaments,
microtubules and
intermediate filaments.
In addition, plectin links the cytoskeleton to junctions found in the
plasma membrane that structurally connect different cells. By holding these different networks together, plectin plays an important role in maintaining the mechanical integrity and
viscoelastic
In materials science and continuum mechanics, viscoelasticity is the property of materials that exhibit both viscous and elastic characteristics when undergoing deformation. Viscous materials, like water, resist shear flow and strain linearly ...
properties of
tissues.
Structure
Plectin can exist in cells as several alternatively-spliced isoforms, all around 500 kDa and >4000 amino acids. The structure of plectin is thought to be a
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ...
consisting of a central
coiled coil
A coiled coil is a structural motif in proteins in which 2–7
alpha-helices are coiled together like the strands of a rope. (Dimers and trimers are the most common types.) Many coiled coil-type proteins are involved in important biological fu ...
of
alpha helices
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
connecting two large globular domains (one at each terminus). These globular domains are responsible for connecting plectin to its various cytoskeletal targets. The carboxy-terminal domain is made of 6 highly homologous repeating regions. The subdomain between regions five and six of this domain is known to connect to the intermediate filaments
cytokeratin
Cytokeratins are keratin proteins found in the intracytoplasmic cytoskeleton of epithelial tissue. They are an important component of intermediate filaments, which help cells resist mechanical stress. Expression of these cytokeratins within epi ...
and
vimentin
Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods.
Vimentin is a type III intermediate filament (IF) protein that is expresse ...
. At the opposite end of the protein, in the N-terminal domain, a region has been defined as responsible for binding to
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
.
In 2004, the exact crystal structure of this
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
-binding domain (ABD) was determined in mice and shown to be composed of two
calponin
Calponin is a calcium binding protein. Calponin tonically inhibits the ATPase activity of myosin in smooth muscle. Phosphorylation of calponin by a protein kinase, which is dependent upon calcium binding to calmodulin, releases the calponin's ...
homology (CH) domains.
Plectin is expressed in nearly all mammalian tissues. In
cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
and
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
, plectin is localized to specialized entities known as
Z-discs.
Plectin binds several proteins, including
vinculin
In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Vinculin is a cytoskeletal protein associated with cell-cell and cel ...
,
DES
Des is a masculine given name, mostly a short form (hypocorism) of Desmond. People named Des include:
People
* Des Buckingham, English football manager
* Des Corcoran, (1928–2004), Australian politician
* Des Dillon (disambiguation), sever ...
,
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
.,
fodrin,
microtubule-associating proteins,
nuclear laminin B.,
SPTAN1
Alpha II-spectrin, also known as Spectrin alpha chain, brain is a protein that in humans is encoded by the ''SPTAN1'' gene. Alpha II-spectrin is expressed in a variety of tissues, and is highly expressed in cardiac muscle at Z-disc structures, co ...
,
vimentin
Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods.
Vimentin is a type III intermediate filament (IF) protein that is expresse ...
and ITGB4
Integrin, beta 4 (ITGB4) also known as CD104 (Cluster of Differentiation 104), is a human gene.
Function
Integrins are heterodimers composed of alpha and beta subunits, that are noncovalently associated transmembrane glycoprotein receptors. Di ...
.
Function
Studies employing a plectin knockout mouse
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
have shed light on the functions of plectin. Pups died 2–3 days after birth, and these mice exhibited marked skin abnormalities, including degeneration of keratinocyte
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
s. Skeletal and cardiac muscle tissues were also significantly affected. Cardiac intercalated disc
Intercalated discs or lines of Eberth are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional syncytium. By con ...
s were disintegrated and sarcomeres were irregularly shapen, and intracellular accumulation of aberrant isolated myofibrillar bundles and Z-disc
A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called musc ...
components was also observed. Expression of vinculin
In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Vinculin is a cytoskeletal protein associated with cell-cell and cel ...
in muscle cells was strikingly down-regulated.
Through the use of gold-immunoelectron microscopy, immunoblotting
The western blot (sometimes called the protein immunoblot), or western blotting, is a widely used analytical technique in molecular biology and immunogenetics to detect specific proteins in a sample of tissue homogenate or extract. Besides detect ...
and immunofluorescence experiments plectin has been found to associate with all three major components of the cytoskeleton. In muscle, plectin binds to the periphery of Z-discs, and along with the intermediate filament protein desmin
Desmin is a protein that in humans is encoded by the ''DES'' gene. Desmin is a muscle-specific, type III intermediate filament that integrates the sarcolemma, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere architecture.
Str ...
, may form lateral linkages among neighboring Z-discs. This interaction between plectin and desmin intermediate filaments also appears to facilitate the close association of myofibrils and mitochondria, both at Z-discs and along the remainder the sarcomere
A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called mus ...
. Plectin also functions to link cytoskeleton to intercellular junctions, such as desmosomes
A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to- cell adhesion. A type of junctional complex, they are localized spot-like ad ...
and hemidesmosomes
Hemidesmosomes are very small stud-like structures found in keratinocytes of the epidermis of skin that attach to the extracellular matrix. They are similar in form to desmosomes when visualized by electron microscopy, however, desmosomes attach t ...
, which link intermediate filament networks between cells. Plectin has been revealed to localize to the desmosomes and in vitro studies have shown that it can form bridges between the desmosome protein, desmoplakin
Desmoplakin is a protein in humans that is encoded by the ''DSP'' gene. Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell conta ...
and intermediate filaments. In hemidesmosomes plectin has been shown to interact with the integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
β4 subunits of the hemidesmosome plaque and function in a clamp-like manner to link the intermediate filament cytokeratin
Cytokeratins are keratin proteins found in the intracytoplasmic cytoskeleton of epithelial tissue. They are an important component of intermediate filaments, which help cells resist mechanical stress. Expression of these cytokeratins within epi ...
to the junction.
Clinical significance
Mutations in ''PLEC'' have been associated with epidermolysis bullosa simplex with muscular dystrophy. A missense variant of PLEC has been recently proposed as a cause of atrial fibrillation in some populations. Isolated left ventricular non-compaction accompanying epidermolysis bullosa simplex with muscular dystrophy was also noted.
Plectin has been proposed as a biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
for pancreatic cancer. Although normally a cytoplasmic protein, plectin is expressed on the cell membrane in pancreatic ductal adenocarcinoma (PDAC) and can therefore be used to target PDAC cells.
See also
* List of target antigens in pemphigus
Circulating auto-antibodies in the human body can target normal parts of the skin leading to disease. This is a list of antigens in the skin that may become targets of circulating auto-antibodies leading to the various types of pemphigus.
...
References
Further reading
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External links
Mass spectrometry characterization of one isoform of PLEC at COPaKB
GeneReviews/NCBI/NIH/UW entry on Epidermolysis Bullosa with Pyloric Atresia
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{{Cytoskeletal Proteins
Plakins