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'''The three-dimensional molecular structure of the desmosomal plaque (2011)'''

Revision as of 22:15, 25 May 2011

Desmosomes

Introduction

Cell junctions occur at points of contact between cells and between cells and the matrix. These junctions are important in the integrity of tissues, cell communication and transport. Cell junctions can be grouped into three main classifications:

  • Occluding junctions that hold epithelial cells together to prevent the leaking of small molecules from one side to the other.
  • Anchoring junctions attach cells to adjacent cells as well as the extracellular matrix.
  • Communicating junctions allow for the transmission of chemical and electrical signals between cells [1]

Desmosomes are classified as anchoring junctions, reasons for which will be explained below.

Structure of a desmosome

Desmosome originates from the greek terms desmo meaning bond and soma meaning body. [2] This etymology reveals the main function of desmosomes which is to bind cells to one another. [3] Desmosomes, also known as macula adhaerens, have a number of other roles including strengthening the internal structure of a cell, sensing environmental cues, regulating tissue homeostasis and assisting in tissue morphogenesis. [3] By indirectly connecting intermediate filaments of adjoining cells, they produce a strong adhesive force which can resist great shear forces. [2] Hence, they are found in such tissues as the myocardium, the bladder, the gastrointestinal mucosa and many epithelia. [4]


This webpage will look into a number of areas to help in the understanding of what desmosomes are, how they work, and what can go wrong when these desmosomes don't work properly. These areas include:

History

Early 19th Century : Light microscopes allowed for the detection of desmosomes within cells.

1864 : Giulio Bizzozero gives the first description of the desmosome. He commented on the small, dense areas that were seen between cells and suggested that these were points of adhesion between adjacent cells. [5] [6]

Guilio Bizzozero

1920 : Josef Schaffer names the structure being seen under the microscope, 'desmosome.' From a greek origin, the name comes from two words meaning 'bond' and 'body.' [7]

1956 : After biological sciences were revived after the world wars, Porter viewed cells using electron microscopy to note that between adjacent cells there were electron dense areas that branched off into cells with fibrous strands. [8] [9]

1974 : By developing new techniques, Skerrow and Matoltsky isolated desmosomes from other cellular components. [10] After running biochemical tests to identify their molecular characteristics, the pair found that the structures had a high glycoprotein content, and that it was these glycoproteins that were responsible for the cell-cell interactions. In doing this, they were able to confirm the hypothesis from 30 years earlier, that desmosomes were in fact junctions between cells. [11] [12]

1981 : Franke and Steinberg characterized and purified the components of desmosomes. [13] [14] [15]

1983 : Using specific antibodies, Cowin and Garrod identify the localisation of desmosomes and note that desmosome distribution is similar between all vertebrates. [16] [17]

1985 : Steinberg, along with his colleagues, begin to isolate plaque proteins. [18] [19]

1988 : Green isolated and analyzed the desmoplakin coding sequence. [20] [21]

1990 : Blaschuk identifies that cadherins contain a tripeptide motif that is crucial in cell adhesion. [22] [23]

1990 Green analyses the amino acid sequence of desmoplakin protein. It was predicted that desmoplakin would have a central alpha-helical, coiled-coil region. [24] [25]

1990 : Koch isolated and characterised the cDNA encoding desmoglein. When screened with cDNA libraries, it was found that they had a high level of homology with cadherins, and as such identified it as a part of the cadherin superfamily. [26] [27]

1991 : Desmocollin, another transmembrane protein in desmosome is isolated and characterised by Collins. Desmocollin has an a form and b form within the cytoplasm, which are produced by alternative splicing of mRNA. [28] [29]

1992 : Stappenbeck and Green define the functional domains of desmoplakin. [30] [31]

1994 : Kouklis demonstrates that the interactions between desmoplakins and intermediate filaments are direct. [32] [33]

1997 : McGrath describes that mutations in Plakophilin-1 leads to ectodermal dysplasia. [34] [35]

1998 : Desmosomal cadherin attachments can be inhibited by peptides that correspond to desmocollin and desmoglein receptor sites (Tselepis). [36] [37]

1999 : Structural studies of the demoplakin gene confirm that the carboxyl terminus acts as an intermediate filament binding site (Kowalczyk). [38] [39]

2000 : Amagai explained the pathogenesis of S. aureus bullous impetigo which is caused by toxin-mediated damage to desmosomes. This was achieved by using antibody immunotherapy. [40] [41]

2001 : Vasioukhin saw that epithelial cells rely on desmoplakin for integrity. [42] [43]

2002 : Windoffer suggests that desmosome structure is dynamic, using fluorescence recovery. [44] [45]

Dynamic Structure of Desmosomes - Video

2003 : Kljuic identifies the genes for desmogleins and desmocollins on the q arm of chromosome 18 in humans. [46] [47]

3D structure of a desmosome.jpg

2003 : He generates a three-dimensional image of a desmosome. [48][49]

2004 : Grossman confirmed the necessity for plakophilin in desmosomal plaques. [50] [51]

2005 : Kimura discovers that desmosomes can be switched from an adhesive and hyper-adhesive state by activation and suppression of Protein Kinase C [52]

2007 : Chidgey and Dawson investigate the role of desmosomes in cancers transforming from tumours to invasive malignancies [53]

2007 : Schmidt suggests that abnormalities that occur within the body may be influenced by changes in signalling properties of desmosomes. [54]

2011 : Al-AMoudi and others show the 3-dimensional structure of a demosomal plaque. [55]

Structure

Structure on a Cellular Level

Structure of a Desmosome and Desmosomal Plaque
Desmosome Electron Micrograph: Bovine Nasal Epidermis

The desmosome, ~300nm in diameter, consists of two distinct domains - the extracellular core domain, ~30-35nm in diameter, and the dense cytoplasmic plaque, ~30-40nm in diameter. [4]

The extracellular core domain, also known as the desmoglea, is made up of the transmembrane proteins - cadherins. [3] There are two types of desmosomal cadherins: desmogleins (DSGs) and desmocollins (DSCs). They extend from the plaque to the extracellular core where they connect to the adjacent cell's cadherins.

The disc shaped plaque, situated parallel to the inner leaflet of the cell membrane, is composed of an outer dense plaque and an inner dense plaque separated by a space of ~8nm. [4] The outer dense plaque is located closer to the plasma membrane than the inner dense plaque and links cadherin tails to desmosomal anchor proteins. [4]

The linker proteins involved are plakoglobin (PG), plakophilin (PKP) and desmoplakin (DP). Extending out from the outer dense plaque are the desmosomal anchor proteins desmoplakins. These form the majority of the inner dense plaque. On the other side of the inner dense plaque is where the intermediate filament network of the cytoskeleton attaches. [56]

Structure on a Molecular Level

Desmosome Diagram

Extracellular Domain

As outlined above, the extracellular domain consists of desmosomal cadherins: desmogleins (DSGs) and desmocollins (DSCs). Cadherins are arranged along the mid-line in ~7nm intervals, with alternating cis (interaction between same cell surface) and trans (interaction between different cell surfaces) dimers causing a tightly packed zipper formation. They are each made up of four extracellular immunoglobulin domains (EC1-4), an immunoglobin extracellular anchor (EA), a transmembrane domain (TM), an intracellular anchor (IA) and additional cytoplasmic domains, which distinguish the cadherin isoforms. [4] Each immunoglobin domain is connected end to end by three calcium ions, forming a curved structure of about 100 degrees. Along the domains are disulfide bonds, O-linked sugars and N-linked sugars. [2]


The cadherin isoforms are composed of different additional cytoplasmic domains as follows [4]:

Desmosomal Cadherins Diagram
Detailed Cadherin Diagram - Image (g) Shows Cis And Trans Interactions


Cytoplasmic Domains
Cadherin Isoform IA ICS IPL RUD DTD
DSCa Present Present - - -
DSCb Present - - - -
DSG1 Present Present Present 5 subunits Present
DSG2 Present Present Present 6 subunits Present
DSG3 Present Present Present 2 subunits Present
DSG4 Present Present Present 3 subunits Present

Note:

There are three isoforms of DSC (1-3), however they splice alternatively into two transcript variants named DSCa and DSCb.

ICS is an intracellular cadherin-like sequence, which binds to plakoglobin.

IPL is an intracellular proline-rich linker.

RUD is repeat unit domains.

DTD is a desmoglein terminal domain


Modulation

Tyrosinase-related protein 2 (Trp2) mediates the cis and trans interactions and is most likely responsible for the binding of cadherins to the plaque. [2] However it is currently unknown whether heterophilic cis and trans or homophobic cis and trans interactions are the main cause of cell adhesion. [57]

The extracellular domain mediates adhesion and whilst the mechanical structure is extremely strong, it is still dynamic since the attachment of both types of cadherins are reliant on Ca2+ levels. During embryonic development of the desmosome, the link between the two cells remains weak. Eventually the link strengths and the cell becomes hyperadhesive. This latter stage is calcium independent, as once protein kinase C is activated by Ca2+ it is able to remain activated in the long-term. Hence this hyperadhesive state will not be affected by changes in Ca2+ concentration. However, the desmosome is able to revert to the earlier state when responding to certain environmental signals to allow for such things as cell migration if regeneration of the epithelia is necessary. [2] [3] The primary morphological attribute which indicates calcium independence is a distinct electron-dense midline that bisects adjoining cell's extracellular core domains. [58] Whereas when desmosomes are calcium dependent the midline is lost and the diameter of the intercellular space decreases by 10%. Potentially this is caused by Ca2+ ions becoming trapped to the cadherins and securing their position into an ordered structure. [58]


Outer Dense Plaque

The dense plaque is made up of two electron-dense zones: an outer dense plaque and an inner dense plaque. The outer dense plaque being lower in density that the inner dense plaque. They are separated by an electron-lucent zone, ~8nm in diameter. The outer dense plaque is located in the cytoplasm, parallel to the plasma membrane. [58] It is ~15-20nm in diameter and characterised by two zones: a ~4nm zone located ~10nm from the plasma membrane and a ~8nm zone located ~20nm from the plasma membrane. The major plaque proteins are plakoglobin (PG), plakophilin (PKP) and desmoplakin (DP).21464301(Please note permission was sought and granted for citing of PNAS Article: The three-dimensional molecular structure of the desmosomal plaque)

Plakoglobin and plakophilin, from the armadillo family of proteins, help to mediate: the attachment of desmoplakin to the intermediate filaments, the arrangement of the plaque components and the signalling in some transduction pathways.


The structure of the major plaque proteins is as follows [4]:

Plakoglobin And Plakophilin Diagram
Desmoplakin Diagram
Major Plaque Proteins
Plaque Proteins Head Arm Repeats Insert Arm Repeats Rod Tail GSR
PG Present 12 - - - Present -
PKPa Present 5 Present 4 - Present -
PKPb Present 5 Present 4 - Present -
DP1 Present - - - Present Present (C-tail) Present
DP2 Present - - - Present Present (C-tail) Present

Note:

Head is an amino-globular head domain with a N terminus.

Tail is a caboxy-terminal tail with a C terminus. In desmoplakin, the tail constits of three plakin repeat domains.

GSR is a glycerine-serine-arginine rich domain.

Insert is a rigid structure producing the bent angle.

The two isoforms of plakophilin, PKP1 and PKP2, both splice into PKPa and PKPb. PKPa is shorter in length than PKPb. For PKPb in comparison to PKPa: in arm repeat three PKP1 version has an additional 21 amino acids, and in arm repeat four PKP2 version has an additional 44 amino acids.

The isoforms of desmoplakin, DP1 and DP2, are characterised by the length of their rod domain - the DP1 rod being ~2/3 longer than the DP2 rod.


Plakoglobin and desmoplakin complexes form an alternating arrangement which acts as a base for the desmosomal cadherins to attach. The cadherin tails bind to the N terminus of desmoplakin before they connecting to the adjoining cell's desmosomal cadherins. Formation of this initial structure is mediated by plakoglobin and plakophilin. For reinforcement the remaining space between the plaque and the plasma membrane is filled by plakophilins. 21464301

Inner Dense Plaque

The inner dense plaque, alike the outer dense plaque, is ~15-20nm in diameter. It is primarily comprised of the junctional complexes, desmoplakins, which tether to the intermediate filaments.[58] The molecular structure of desmoplakin is outlined in the above 'Outer Dense Plaque' section, as the protein spans through both parts of plaque. The leading theory is that the glycine-serine-arginine domain, adjacent to the carboxy-tail terminus of desmoplakin, regulates the attachment of the keratin intermediate filaments. The molecular structure of the plaque with its components having both medial and lateral connections, is thought to be one of the main reasons for the desmosome's adhesive strength.21464301

Function

Desmosome as cellular adhesion junction

Desmosomes are important components of many types of epithelia. These structures are permanent and prevent leaking of small molecules through the surface as well as resisting shearing forces. [59] Shearing forces encountered particularly in staraified, squamous, keratinised epithelium of the epidermis as well as in muscular layers of the heart.

KeratinF9.png

In a normal state, desmosomes establish continuity or confluence of epithelial sheets [60] Cell to cell desmosome spot junctions contribute strength to the barrier function of epithelia, a function that is largely brought about by the Zonula Adherens. [61] Multiple desmosome adhesion complexes located on the plasma membrane bond cells to each other and in this way a confluent epithelial sheet is formed, of note is its individual cellular positional stability.

There are many aspects of the structure of demosomes that are still not completely undertood. However, it is known that cytoplasmic surface molecular interactions link extracellular transmembrane cadherins proteins with intracellular intermediate keratin filaments, located inside the cells as part of the their cytostructure.[62]

The attachment plaque mediates adhesion of these intermediate filaments with the extracellular cadherin tails of the plasma membrane. [63] Electron microscopy (EM) and specialised techinque that makes it possible to view these structures. From this it has been possible to hypothesise how the extracellular core domain bind to desmoglein and desmocollin in a zipper-like fashion at the midline to the cells.

The tails of these calcium dependent cadherins bind through the plasma membrane and into the cytoplasm of the adjacent cells. This forms a connection between a cytoplasmic plaque within each cell and anchors them together.[64] Desmoplakin, plakoglobin and plakophilin are proteins that form the dense plaque in the cytoplasm that functions as the bondage site to the intermediate filaments; thus locking the extracellular cadherins with the interior of the cell by providing an anchoring point for both [65]

Desmosome protein composition can differ in the presence of the isoforms of core and other accessory proteins, and to their relative amount present. [66] It is in this way that desmosomes can influence the specific way cells bind to the cytoskeleton of another, thus influencing tissue supracellular architecture.[67] [68] [69] [70] For instance meningothelia differs from myocardium in terms of desmosome protein composition. The adhesive qualities in these contrasted tissues differs. [71]

Changes in adhesive state influence function of epithelia

The adhesive state of the desmosome can change in accordance with the state of the epithelia in which they are found[72]


During embryogenisis, epithelial differentiation and wound healing the adhesives qualties of the proteins were found to change.[73] The desmosome allowed cellular movement. For example in wound healing the dissolving of desmosomes allowed keratinocytes to migrate into areas of epithelial injury. [74]

Epidermis epithelial cell wound healing involves changes in desmosome function

Hemidesmosomes

Ultrastructure of tracheal hemidesmosomes.

Hemidesmosomes like the name suggests are extremely similar to the desmosomes in the fact that they are specialized junctional complexes. However unlike desmosomes which specialises in cell to cell adhesion hemidesosomes contribute to the attachment of epithelial cells to the underlying basement membrane in stratified and other complex epithelia, such as the skin, the cornea and both parts of the respiratory and gastrointestinal tract. Hemidesomosomes are multiprotein complexes, and it is these proteins that help determine the cell–stromal coherence of the hemidesomoses. The proteins also provide the cells with cues critical for the polarization, spatial organization and tissue architecture.

The functional activity can be modulated, however the regulation of the adhesive interaction between the hemidesmosomes and the basement membrane below is essential in various normal biologic process, such as wound healing and tissue morphogenesis. The regulation of hemidesmosome function occurs via many different factors for example extracellular matrix (ECM) proteins and growth factors. To add to this the 6 4 integrins in the hemidesmososme also act as regulatory components and this done by transducing signals that profoundly affect the cellular function. Thus hemidesmosomes are not only structural adhesion complexes but also serve as signalling devices via the 6 4 integrin which affecting cell phenotype.

Structure of Hemidesmosomes





Regulation

Calcium

Calcium ion levels are integral in junction assembly. In vitro, extracellular calcium levels have been found to trigger the formation of the junctions. [75] After cells that have been incubated in low calcium medium, were switched into a medium containing standard calcium concentrations, the formation of desmosomes was seen as soon as 5 minutes. [76] The deregulation of calcium levels within cells have been associated with junctional defects. Hailey-Hailey disease and Darier's disease are caused by defects in Golgi and ER calcium pumps. [77] These both lead to a loss of integrity in skin epithelium, due to a lack of cell-cell attachment via desmosomes. [78] [79]

Calcium regulation


Desmoplakin

Desmoplakin

It has been suggested that regulation of desmosome assembly is closely associated with the assembly of adherens junctions. [80] Desmoplakin is the only protein, so far identified, that is common to both junctions. In vitro, cells that did not express desmoplakin were unable to localise the proteins specific for the adherens junctions and the desmosomes. [81] Thus, it has been suggested that it plays a role in segregating the proteins relative to each junction and so affecting assembly.


Phosphorylation

Phosphorylation has been found to be largely involved in activating and deactivating desmosome assembly. It has been suggested that protein kinase C (PKC) is involved in the regulation of this action. [82] PKC inhibition is required for desmosome assembly to occur, that is, dephosphorylation encourages formation. Phosphorylation onto serine of desmoplakin by protein kinase C can lead to the disassembly of the cytoskeleton, junctions, and a loss of cell-cell contact. An increase in level of serine phosphorylation has also been linked with an increase in junction solubility of the desmoplakin. This suggests that phosphorylation may play an integral role in the dissociation of the desmosomal plaque from the keratin filaments. [83] The outcome of plakoglobin (an important desmosomal protein) is also largely dependent on its phosphorylation. [84]

Desmosomes and Disease

Investigations into function through knock out gene models

Changes in desmosomes in transgenic mice

Knock out gene animal model investigations into the absence of desmosome protein isoforms in various epithelia have shown how they may be involved in associated disease states of the epithelia in which they are located, thus giving a window into their non pathological function. It has been suggested that the distribution of one or other desmosome protein isoforms in various epithelia is due to the degree of adhesion necessary according to any stresses encountered at that location. [85]

Studies into the function of these protein isoforms has also suggested they may act as influencing the function of the associated epithelia itself outside of the mere adhesive function.

An example of this is desmoplakin 1 which is found in all desmosomes including the endothelial cells of of capillaries. [86]

During tumourous cancer growth, in such cancers as oropharyngeal and breast cancer, desmoplakin type 1 function becomes down regulated and aids tumour growth by stimulating angiogenesis or the growth of new blood vessels from existing vascular structures [87]

This down regulation means that now the desmosomes may function in tumour cell proliferation.

It is the abnormal over or under functioning of desmosome proteins that highlights its specialised adhesion function.

Related Diseases

Disease Description Image
Bullous Impetigo Impetigo is a skin condition common in school children, especially those who play close contact sports. This skin condition is also known as school sores and is caused by a bacterial infection. Bullous Impetigo causes fluid-filled blisters in the skin, primarily on the trunk, arms and legs. These blisters are painless and scab over before they heal. [88]

Staphylococcous aureas is the bacteria responsible for inducing bullous impetigo through its release of exfoliative toxins. When mice are injected with exfoliative toxin from S. aureas blistering of the skin is noticed and under an electron microscope it is possible to see that the desmosomes within the epithelia have been torn apart. [89] Exfoliative toxin A has been proven to cause the blistering through its serine protease activity. The blisters of Bullous Impetigo are localised to the superficial epidermis, and as such it is possible to confirm that the exfoliative toxin A is specific to Desmoglein-1. Desmoglein -1 is present not only in the superficial layers of epithelium but also in the deeper layers. Desmoglein-3 however is not present in the superficial layer. Given that blistering does not occur in the deeper layers it is possible to assume that Desmoglein-3 compensates for the destruction of Desmoglein-1. Experimental results have shown that on injection of exfoliative toxin A, Desmoglein-1 was damaged while Desmoglein-3 remained unaltered. This was done by addition of antibodies for Desmoglein-1 and Desmoglein-3 followed by immunoflurorescence. [90]

Bullous Impetigo has similar symptoms to many drug reaction symptoms. The differentiation between these is possible through a skin biopsy. Bullous impetigo will only have blistering on the superficial layers while a drug reaction will see blistering in the lower layers of the epithelium as well as necrotic keratinocytes. Treatment usually consists of a course of antibiotics but it is important to consider that antibiotic-resistant strains of S.aureas are quite common. [91]

Bullous Impetigo

Pathophysiology of Bullous Diseases - video

Palmoplantar Keratoderma Desmoplakin is the most abundant protein in desmosomal plaques, therefore having an important role in linking the intermediate filaments to the plasma membrane of cells in the epidermis and heart. Palmoplantar Keratoderma is skin condition that results from a mutation on the gene that encodes desmoplankin. Mutations can either lead to a loss of the gene completely, or cause haploinsufficiency. This genetic disorder was noted in patients who were affected by this skin condition. [92]

Palmoplantar Keratoderma is a rare condition. It is characterised by hyperkeratosison the palms of the hands and soles of the feet. This leads to a distinctive thickening of the skin, often in a striated pattern. When viewed under a light microscope, affected areas showed an increase in space between the keratinocytes. Moreover, the desmosomes appeared to be smaller and less were found when compared to a normal section of skin from the same patient. [93]

Keratoderma
Arrhythmogenic Right Ventricular Cardiomyopathy Arrhythmogenic Right Ventricular Cardiomyopathy is a cardiomyopathy is related to the functioning of desmosomes. When cell adhesions are compromised, the cardiac tissue loses its integrity. As a result of this, the body attempts to repair the damage by replacing the tissue with fibrofatty tissues. This presents a number of problems for the cardiovascular system and results in some fatal complications. [94] This condition is more common in individuals under the age of 30. Clinical symptoms present with misarrhythmias or in some cases, sudden death. Most prominent symptoms are seen during or after intense physical activity when the heart is put under stress.
Arrythmogenic Right Ventricular Cardiomyopathy

Current Associated Research

Human Epidermal Desmosome-Enriched Tissue Fractions for Analytical and Prospective Studies (2011)

This report describes a method that has now been adapted to the human epidermis which allows for the isolation of desmosomes in small tissue fraction as the previous methods used, which was developed for animal skin did not work as efficiently on human tissue. First of all the desmosomes were enriched by t he association of two incubation step in acidic solution which consisted of the detergent NP-40 at 2 different concentration. This was then followed by sonication. The suspension was then centrifuged twice: the first time was to remove heavy cell fragments. It was the centrifuged again on a 16000g on a discontinuous sucrose gradient. A desmosome - enriched fraction was then collected at approximate 30-50% sucrose gradient levels. Both immunelectron microscopy and western blotting was then used on the desmosome -enriched fraction to show that the central part of the desmosomes are preserved as well as retaining their antigenicity component. This method can be used to both immunise animals as well as created new antibodies that are directed toward the desmosomal components. The hope of this study is that it allows for new studies to be done on a not well understood topic: The incorporation of molecules into the desmosome core which could be then target much easier.[95]


Lack Of Plakoglobin Leads To Lethal Congenital Epidermolysis Bullosa: A Novel Clinico-Genetic Entity (2011)

As stated above epidermal integrity is essential for skin functions. This integrity is actually maintained by adhesive structure between keratinocytes, mainly the desmosomes and adherens junctions. These adhesive structures provide resistance against mechanical stress and regulate the formation of the skin barrier. Plakoglobin is one of the constituents in both types of intracellular junctions and thus has a numerous number of interaction partners and mutation in it gene via studies previous conducted gas been associated with mild cutaneous disease, keratoderma, arrthythmogenic heart disease and palmoplantar.


In this article, Pigros et al. report a so called novel lethal phenotype cause by a nonsense mutation in the gene that codes for plakoglobin [Junction Plakoglobin (JUP)] however this mutation and its effects have never been described before in either human or murine. The patient in this article suffered from the severe congenital skin fragility with generalised epidermolysis and on top of this massive transcutaneous fluid loss. Yet the sufferer did not ever present to health care professionals with cardiac dysfunction. It was noticed when immimofluroescence and immunoblot analysis was done that unlike JUP mutations before where truncated plakoglobin was present, there was a complete loss of plakoglobin in the skin. Thus only a few abnormal desmosomes were formed and no adhesion structures between keratinocytes were recognisable. The role of distribution of desmosomal components was extremely affected which suggest that plakoglobin play a essential role for plakoglobin in demosomal assembly. Thus this article reinforces on a whole new level the fundamental role of plakoglobin in epidermal cohesion. [96]


Wide Spectrum of Desmosomal Mutations in Danish Patients with Arrhythmogenic Right Ventricular Cardiomyopathy (2010)

In the study, 65 unrelated patients with Arrhythmogenic right ventricular cardiomyopathy (ARVC), a lethal disease which is characterised by Ventricular tachyarrhythmias with right and/or left ventricular involvement and fibrofatty infiltrations in the myocardium were screened for mutations in the number of genes that code for desmosomes which include desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP) and plakophilin-2 (PKP2) and TGFb3. The results of the study was the identification of 19 different mutations with all genes that code for desmosomes being affected apart from TGFb3 which showed no genomic rearrangements or mutations. The conclusion of the study was that 33% of patients in this Danish cohort with ARVC carried desmosomal mutations with a surprisingly wide mutation spectrum. A substantial proportion of patients carried more than one mutation. Our study supports comprehensive desmosomal mutation screening beyond the first encountered mutation, whereas routine screening for genomic rearrangements does not seem indicated.[97]


Desmosomes: new perpetrators in tumour suppression (2011)

It has long been thought that adherens junctions, which are intracellular junctions, played a role in epithlial integrity during tumour progression due to their down-regulation at this time. Recent studies have used genetically mice to demonstrate the role of desmosomes in tumour growth. This study has shown that desmosomes are actually down-regulated before the adherins junctions and so a two-step process has been considered. [98]

3D molecular structure of the desmosomal plaque

The three-dimensional molecular structure of the desmosomal plaque (2011)

Until now, the exact structure of desmosomal plaques has remained a mystery. Although the proteins involved in the structure have previously been identified, the architechture was unknown. Al-Amoudi et al, used cyroelectron tomography of epithelial desmosomes to acheive this goal. The main advantage of this technique, was that no heavy metal staining was used, and so a higher resolution image could be produced. However, due to the cutting of cyrosections to observe the structure, artifacts such as knife marks, were prominent. These artifacts and challenges were eventually overcome, and 3D imaging was used to produce a detailed image, never seen before. [99]

Glossary

A

Alpha Helix is a secondary structural motif of proteins. The amino acids are arranged in a right-handed helix. The backbone it made up of N-H, the contributing hydrogen bonds strengthening the structure.

Anchoring Junctions is a type of cell junction that attaches cells to adjacent cells as well as to the extracellular matrix.

Antibody is a protein produced by B cells, used to identify and neutralize foreign material in the body.

B

C

Cadherins are a group of transmembrane proteins. They are heavily involved in cell adhesion. As the name suggests, they are dependent on calcium for their regulation.

Carboxy Terminus is the end of an amino acid chain with a free carboxyl group.

cDNA is also known as complementary DNA. It is produced from mature mRNA by reverse transcriptase and DNA polymerase.

Communicating Junctions allow for the transmission of chemical and electrical signals between cells.

D

Desmocollin is a desmosomal cadherin. It is expressed by the human genes DSC1, DC2 and DSC3.

Desmoglein is a member of the cadherin family. They are involved in the formation of desmosomes and expressed by genes DSG1, DSG2, DSG3 and DSG4

Desmoplakin is a protein associated with desmosomes, anchoring the intermediate filaments to the desmosomal plaques.

Desmosomes are a type of cell junction that indirectly connect the intermediate filaments of adjoining cells. Their main function is to bind cells to one another.

Dysplasia refers to abnormal development. It is usually associated with a neoplastic process.

E

Electron-Lucent Zone

Electron Microscopy

Epithelium

F

Fluorescence Recovery


G

Glycoprotein


H

Hemidesmosomes are a type of cell junction that attaches epithelial cells to the underlying basement membrane in stratified and other complex epithelia.

Homology

Hyper-adhesion

I

Immunotherapy

Intermediate Filaments

M

Malignancy

mRNA Splicing

O

Occluding Junctions hold epithelial cells together to prevent the leaking of small molecules from one side to the other.

P

Pathogenesis

Plakophilin

Plaque Protein

T

Transmembrane Protein

Tripeptide

Images and Videos

[http://www.pnas.org/content/early/2011/03/30/1019469108.full.pdf The three-dimensional molecular structure of the desmosomal plaque]

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Coordinator Comment to all Groups

I will add a general comment that will be the same to all groups under this heading.

Referencing Extension Problem

--Mark Hill 13:16, 3 May 2011 (EST) As mentioned in the lecture, I am aware of the referencing extension problem on your project pages. I have the following temporary solution, of removing the extension, so that groups can continue to add content to their project pages. I am also giving everyone a 1 week extension before the peer assessment.

This should only be done if your project page is not allowing you to save changes!

A. The Easy Way....

The following 4 steps can be done on the webpage or select all content in edit mode, copy and paste into a text editor. All steps must be completed before you attempt to save.

  1. In page edit mode, find all <pubmed> reference tags.
  2. Replace this tag with [http://www.ncbi.nlm.nih.gov/pubmed/ Note, there should be no spaces between the internet address and the pmid number.
  3. Now find all </pubmed> reference tags.
  4. Replace this second tag with ]

This will generate a numbered reference list that we can later fix up.


B. The Better Looking Result....

Whatever is between the <ref> </ref></pubmed> tags is what will appear in your reference list, so you can format the reference and link to appear in your reference list.

2011 Projects: Synaptic Junctions | Gap Junctions | Tight Junctions | Desmosomes | Adherens Junctions | Neuromuscular Junction