Lecture 24 Flashcards
What is the funciton of desmosomes?
Provides strong adhesion between epithelial and muscle cells
What do desmosomes look like?
Disc-shaped (spots) between adjacent cells
Who first identified desmosomes?
Inititally identified by Guilio Bizzozero
He was an Italian pathologist
Also identified and correctly assessed the function of platelets
Identified bone marrow as the site for BC
What were desmosomes initially called?
Desmosomes were intitally called “Nodes of Bizzozero”
Who named the term “desmosomes”?
Josef Schaffer coined the term “desmo” meaning bond and “soma” meaning fastening (body)
What is the function of the molecular components of desmosomes?
Confer mechanical strength to tissues
What are some desmosome diseases?
Desmosome diseases –> major blistering
What are some transmembrane proteins in desmosomes?
Desmocollin and Desmoglein
What do these transmembrane proteins do?
Used to link plasma membrane together
They are desmosomal cadherins
Calcium dependant
Cadherins have 5 extracellular domains
How do desmocollin and desmoglein interact?
Desmocollin can interact with Desmoglein (eg. DSC1 interacts with DSG2)
How many of these genes do mammals have?
3 desmocollin genes
4 desmoglein genes
Which of the two are alternatively spliced?
Desmocollin genes are also alternatively spliced
What are in most desmosomes?
Desmocollin 2 and desmoglein 2 are in most desmosomes
What happens in a Desmocollin-3 null mouse?
The mouses skin ripped off when it was born at the site of the wound, the desmosomal plaque does not connect to the other side which leads to skin ripping off
Everything is fine until there is mechanical stress
What is the desmocollin-3 site-directed skin null mouse?
Select the gene that is only found in the skin, and make the knock-out occur there, internally the mouse is fine but the skin rips off
What did the baby mice cause in the Desmoglein-3 null mouse?
Baby mice caused nipple erosion on the mother mouse
D and E- no mechanical force
B- the rips in the cells
What is Plakoglobin also known as?
Y (gamma) catenin
What is the function of plakoglobin?
Links desmocollin and desmoglein to desmoplakin, plakophilin, and intermediate filaments
Binds to the intracellular cadherin specific domain (ICS) of the desmocollins and desmogleins
What does PKP1 (Plakophilin) do?
PKP1: binds to desmoglein, desmoplakin and intermediate filaments
Thought to be responsible for clustering the proteins that make the electron dense plaque of the desmosomes
What is the clinial disease of PKP?
People with mutations to PKP1:
Ectodermal dysplasia- affects development of teeth, nail, sweat glands and hair
Skin Fragility Syndrome- huge amount of skin blistering (fragile)
What are mutations in PKP2 null mice like?
PKP2 null mice are embryologically lethal due to cardiac defects and “fragility of the myocardium”
Intermediate filaments release as it can’t bind well through desmoplakin
What is the most abundant protein at the desmosome?
Desmoplakin
What is desmoplakin needed for?
Needed to anchor the desmosome plaque to intermediate filaments
What are the 2 proteins in desmoplakin?
Desmoplakin 1 (250kD) and desmoplakin 2 (251kD)
Why is desmoplakin so important?
Very important for maintaining the heart because it is at intercalated discs (joins cardiomyoctes together)
Do KO desmoplakin mice die?
KOs die at E6.5, have less desmosomes
Do desmosomes bind to intermediate filaments?
Desmosomes that exist do not bind to intermediate filaments
What is the similarity and difference between desmosomes and hemidesmosomes?
Hemidesmosomes and desmosomes morphologically look similar, but are very different at the molecular levels
What kind of adhesion do desmosomes and adherens junctions use?
Demsosomes (and adherens junctions) use cadherin based adhesion
How do hemidesmosomes bind to the ECM?
Hemidesmosomes use integrins to attach the intermediate filaments cytoskeleton to the extracellular matrix (Laminin) at the base of the cell
What are integrins?
Many types in the cells
What is the integrin Alpha6beta4 needed for?
Alpha6beta4 needed for hemidesmosome assembly and stability
What can alter Alpha6beta4 integrin signalling?
The absense of Keratin 8 and 18 intermediate filaments can alter Alpha6beta4 integrin signalling and enhance cell migration
What does less keratin mean?
Less keratin= less hemidesmosome= faster cell motility
What is Laminin?
Many types, but Laminin 5 is in the basal lamina (basement membrane)
What is BPAG2?
It is a hemidesmosome
It is a collagen (specifically collagen 17A1)
It is named for bullous pemphigoid antigen-2, a skin dsease caused by autoantibodies to Collagen 17A
