Collagen XVII
Encyclopedia
Collagen XVII, previously called BP180, is a transmembrane protein which plays a critical role in maintaining the linkage between the intracellular and the extracellular structural elements involved in epidermal adhesion .
XVII is a homotrimer of three alpha1(XVII)-chains and a transmembrane protein in type II orientation. Each 180 kD a-chain contains a globular intracellular domain of approximately 70 kDa, which interacts with beta4-integrin
, plectin
, and BP230 and is necessary for the stable attachment of hemidesmosome
s to keratin
intermediate filaments. The large C-terminal ectodomain with a molecular mass of approximately 120 kDa consists of 15 collagenous subdomains, characterized by typical collagenous G-X-Y repeat sequences, flanked by 16 short non-collagenous stretches. The overall structure of the ectodomain is that of a flexible, rod-like triple helix
with a significant thermal stability . The membrane proximal part of the ectodomain, within amino acids 506-519, is responsible for binding to alpha 6 integrin, this binding seems to be important for the collagen XVII integration into hemidesmosomes. The largest collagenous domain, Col15, which contains 232 amino acids (amino acids 567-808), contributes significantly to stability of collagen XVII homotrimer. The C-terminus of collagen XVII binds to laminin 5, and correct integration of laminin 5 into the matrix requires collagen XVII.
, an autosomal recessive skin disease with variable clinical phenotypes. Morphological characteristics of junctional epidermolysis bullosa are rudimentary hemidesmosomes and subepidermal tissue separation. Clinical hallmarks, in addition to blisters and erosions of the skin and mucous membranes, include nail dystrophy, loss of hair, and dental anomalies. Collagen XVII also plays a role as an autoantigen in acquired subepithelial blistering disorders . Most immunodominant epitopes lie within the NC16A domain, and the binding of the autoantibodies perturbs adhesive functions of the collagen XVII, and this (together with inflammation-related processes) leads to epidermal-dermal separation and skin blistering.
with Keratin 18
, Actinin alpha 4
, Dystonin
, Actinin, alpha 1, CTNND1
and ITGB4
.
Structure
CollagenCollagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
XVII is a homotrimer of three alpha1(XVII)-chains and a transmembrane protein in type II orientation. Each 180 kD a-chain contains a globular intracellular domain of approximately 70 kDa, which interacts with beta4-integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
, plectin
Plectin
Plectin is a giant protein found in nearly all mammalian cells which acts as a link between the three main components of the cytoskeleton: actin microfilaments, microtubules and intermediate filaments. In addition plectin links the cytoskeleton to junctions found in the plasma membrane that...
, and BP230 and is necessary for the stable attachment of hemidesmosome
Hemidesmosome
Hemidesmosomes are very small stud- or rivet-like structures on the inner basal surface of keratinocytes in the epidermis of skin. They are similar in form to desmosomes when visualized by electron microscopy. While desmosomes link two cells together, hemidesmosomes attach one cell to the...
s to keratin
Keratin
Keratin refers to a family of fibrous structural proteins. Keratin is the key of structural material making up the outer layer of human skin. It is also the key structural component of hair and nails...
intermediate filaments. The large C-terminal ectodomain with a molecular mass of approximately 120 kDa consists of 15 collagenous subdomains, characterized by typical collagenous G-X-Y repeat sequences, flanked by 16 short non-collagenous stretches. The overall structure of the ectodomain is that of a flexible, rod-like triple helix
Triple helix
In geometry, a triple helix is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. Structures in the form of a triple helix include:* collagen helix...
with a significant thermal stability . The membrane proximal part of the ectodomain, within amino acids 506-519, is responsible for binding to alpha 6 integrin, this binding seems to be important for the collagen XVII integration into hemidesmosomes. The largest collagenous domain, Col15, which contains 232 amino acids (amino acids 567-808), contributes significantly to stability of collagen XVII homotrimer. The C-terminus of collagen XVII binds to laminin 5, and correct integration of laminin 5 into the matrix requires collagen XVII.
Pathology
Mutations in the human collagen XVII gene, , lead to the absence or structural alterations of collagen XVII . The functional consequences include diminished epidermal adhesion and skin blistering in response to minimal shearing forces . The disorder is called junctional epidermolysis bullosaEpidermolysis bullosa
Epidermolysis bullosa is an inherited connective tissue disease causing blisters in the skin and mucosal membranes, with an incidence of 1/50,000. Its severity ranges from mild to lethal. It is caused by a mutation in the keratin or collagen gene....
, an autosomal recessive skin disease with variable clinical phenotypes. Morphological characteristics of junctional epidermolysis bullosa are rudimentary hemidesmosomes and subepidermal tissue separation. Clinical hallmarks, in addition to blisters and erosions of the skin and mucous membranes, include nail dystrophy, loss of hair, and dental anomalies. Collagen XVII also plays a role as an autoantigen in acquired subepithelial blistering disorders . Most immunodominant epitopes lie within the NC16A domain, and the binding of the autoantibodies perturbs adhesive functions of the collagen XVII, and this (together with inflammation-related processes) leads to epidermal-dermal separation and skin blistering.
Shedding
Collagen XVII is constitutively shed from the keratinocyte surface within NC16A domain by TACE (TNF-Alpha Converting Enzyme), metalloproteinase of the ADAM family . The shedding is lipid raft dependent . Collagen XVII is extracellularly phosphorylated by ecto-casein kinase 2 within the NC16A domain, phosphorylation negatively regulates ectodomain shedding .Interactions
Collagen, type XVII, alpha 1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Keratin 18
Keratin 18
Keratin 18 is a type I cytokeratin. It is, together with its filament partner keratin 8, perhaps the most commonly found products of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic...
, Actinin alpha 4
Actinin alpha 4
Alpha-actinin-4 is a protein that in humans is encoded by the ACTN4 gene.-Interactions:Actinin alpha 4 has been shown to interact with PDLIM1, Sodium-hydrogen exchange regulatory cofactor 2, Collagen, type XVII, alpha 1, CAMK2A, CAMK2B, MAGI1 and TRIM3.-Further reading:...
, Dystonin
Dystonin
Bullous pemphigoid antigen 1, isoforms 1/2/3/4/5/8 is a protein that in humans is encoded by the DST gene.-Interactions:Dystonin has been shown to interact with Collagen, type XVII, alpha 1, DCTN1 and Erbin.-Further reading:...
, Actinin, alpha 1, CTNND1
CTNND1
Catenin delta-1 is a protein that in humans is encoded by the CTNND1 gene.-Interactions:CTNND1 has been shown to interact with Beta-catenin, FYN, Collagen, type XVII, alpha 1, PTPN6, YES1, PTPRJ, VE-cadherin, MUC1, CDH1, CDH2, PTPRM, Cortactin, Nephrin, ZBTB33 and PSEN1.-Further reading:...
and ITGB4
ITGB4
Integrin, beta 4 also known as CD104 , is a human gene.-Interactions:ITGB4 has been shown to interact with Collagen, type XVII, alpha 1, EIF6 and Erbin.-Further reading:...
.