Basement Membrane Zone Flashcards
What is the function of the BMZ?
Adhere the epidermis to the dermis
What stains can be used to highlight the BMZ?
PAS - purplish
What is the basement membrane?
The thin line seen with light electron microscopy between the epidermis and the dermis
What is the basal lamina?
Dense sheet-like structure seen with electron microscopy which is secreted by epidermal keratinocytes
Traditionally composed of lamina lucida and lamina densa
What is the basement membrane zone?
The complex structure which can be seen with electron microscopy and spans the space between the base of the basal keratinocytes to the underlying dermal matrix.
Consists of:
- Intermediate filaments
- Hemidesmosomes
- Anchoring filaments
- Lamina densa
- Anchoring fibrils
What are the four levels that the BMZ can be divided into when viewed via electron microscopy?
Basal keratinocytes
Lamina lucida (artifact of processing)
Lamina densa
Sublamina densa/superficial papillary dermis
What is the lamina lucida?
Traditionally one of the layers of the basal lamina but is really an artifact caused by dehydration fixation for electron microscopy - is not present when processed with chemical fixation
More historical than scientific significance
Contains extracellular domains of Col XVII, a6b4 integrin and CD151 as well as anchoring filaments (laminin-332)
What are the functions of the cytoskeleton within the basal keratinocytes?
- Structural support
- Cell movement
- Intercellular transport
- Anchor cells
What types of filaments compose the cytoskeleton within the basal keratinocytes?
1) Microfilaments (7nm diameter)
2) ** Intermediate filaments (10 nm diameter)
- most important for the BMZ
3) Microtubules (25 nm diameter)
What are the molecules that intermediate filaments bind to in the BMZ?
- Plectin
- BPAG1e
Both part of the plakin family
Describe the structure of a hemidesmosome.
Two plaque structure (inner and outer) within basal keratinocytes
Composed of at least 5 distinct molecules
- BPAG1e (inner)
- Plectin (inner)
- α6β4 integrin (outer, extends into lamina lucida - transmembrane)
- collagen XVII (outer, extends into lamina lucida -transmembrane)
- CD151
Describe BPAG1e aka BP230
230 kDa, found in the inner plaque of hemidesmosomes
Dumb-bell shaped with 3 domains:
1) plankin-like globular (amino-terminal)
- interacts with β4-subunit of α6β4 integrin and collagen XVII
2) coiled-coil rod
3) intermediate filament binding domain (carboxyl terminal
Functions:
- structural integrity
- signaling and regulation of cell polarity and migration
- not required for hemidesmosome/BMZ assembly
- no associated genetic disease?
Describe plectin
450-533 kDa, found in the inner plaque of hemidesmosomes
Interacts with all keratinocyte cytoskeletal proteins
4 domains:
1) amino-actin binding domain
- binds the β4-subunit of α6β4 integrin (primary)
2) plankin domain
- also binds the β4-subunit of α6β4 integrin
3) a-helical coiled-coil rod
4) plankin-repeat domain (carboxyl terminal)
- binds intermediate filaments
- also binds the β4-subunit of α6β4 integrin
Functions:
- Structural integrity
- Scaffold for signaling molecules
Describe α6β4 integrin
Transmembrane protein
260-360 kDa, found in the outer plaque of the hemidesmosome extending into lamina lucida
a3b1 also exists and is found elsewhere, not big in the BMZ
Alpha chain has 6 domains (shorter):
- one end (7-bladed b-propeller) has multiple calcium binding sites
- other end (intracellular/cytoplasmic), binds collagen XVII and CD151
Beta chain has 7 domains (longer):
- one end binds to laminin-332
- other end (intracellular/cytoplasmic) binds intermediate filaments, BPAG1e, collagen XVII, and plectin
Functions of integrins:
- Structural integrity
- Epidermal adhesion, proliferation, and differentiation
- B1 subunit is important for hair growth and wound healing
Describe collagen XVII aka BP180
Transmembrane protein
180 kDa, found in the outer plaque of the hemidesmosome extending into lamina lucida and lamina densa
Is cleaved extracellularly into 120 kDa LAD-1 and 97 kDa LABD97 (functions unknown) which are associated with linear IgA bullous dermatosis
Has 4 domains which can be visualized as a globular head, rigid central rod region and flexible tail
- intracellular aspect (head) binds to plectin, BPAG1e, and a6b4 integrin (b4)
-extracellular NC16A domain binds to α6β4 integrin (α6) and laminin-332
Functions:
- structural integrity
- basal cell migration and adhesion
- enamel formation
Describe CD151
29-32 kDA, found in outer plaque of hemidesmosome
6 functional domains
- amino and carboxyl ends are both found within the basal keratinocyte membrane
- long extracellular loop which interacts with α6β4 integrin (a6)
Will cluster and interact with each other and integrins to form a tetraspanin web
Describe anchoring filaments
~800 nm wide structures seen within the lamina lucida on electron microscopy
-composition is controversial but may include Col XVII, a6b4 integrin, CD151, Laminin-332** (believed to be the main component), or laminin-311
Describe laminin-332
410 kDa
Large glycoproteins composed of 3 chains (a, b, y) connected with disulfide bonds
Laminins are secreted by keratinocytes as a precursor that then assembles
-One end (globular carboxyl domain) binds α6β4 integrin
-Other end binds Col VII and other laminins with one side and Col IV, VII, XVII, and perlecan
Other laminins (511 and 311) are also found in the BMZ but this is considered the prototype
Functions:
- structural integrity
- embryogenesis
- tissue morphogenesis
- regulation of proliferation and differentiation
- tumorigenesis
What is the lamina densa?
The electron dense zone seen on electron microscopy below the lamina lucida
Contains collagen IV, laminin-332, nidogen, and perlecan
Also contains portions of a6b4 integrin
Is made of lattices of collagen IV molecules (majority) and others of laminin-332 molecules
Describe collagen IV
Made in the rough ER and secreted into the basement membrane
Made of 3, 400 nm alpha chains that self assemble into a triple helical structure with 3 domains
Differs between embryonic and adults
There are a variety of formations due to the alpha chains which can be found in various places, one variant found just in the glomerulus
Resembles pro-collagen because has amino and carboxyl terminal
Complex binding with other BMZ components (laminin-332, perlecan, nidogen, fibronectin, collagen VII)
Self assembles into 3 dimensional hexagonal lattice structures
Functions:
- structural integrity
- tumorigenesis
Describe nidogen
1500-200 kDa, found in the lamina densa
Sulfated monomeric glycoprotein with 4 domains
- One end binds Col IV and perlecan
- Other end binds laminin 311
Why the lamina densa stains with PAS
Functions:
- structural integrity
- embryogenesis
- tumorigenesis
Describe perlecan
A heparan sulfate proteoglycan found in the lamina densa
680-770 kDa
Has covalently bonded glycosaminoglycan side chains
- chonrdroitin sulfate
- dermatan sulfate
- keratan sulfate
- heparin
- heparan sulfate
Central core has 5 domains
- bind to nidogen, collagen IV and other less common molecules
Functions:
- negative charge for the basement mebrane
- structural integrity
- permeability barrier
- regulation of angiogenesis, etc
- Cellular adhesion
- Epidermal morphogenesis
- Tumorigenesis
Describe the anchoring fibrils
Found in the sublamina densa/superficial papillary dermis
Semi-circular loops of collagen VII which resemble Velcro
The lattices of the lamina densa weave through them
Describe collagen VII
290 kDA triple helical molecules, found in the lamina densa and sublamina densa
Makes up anchoring fibrils
Has 3 main domains
Self-assembles into antiparallel dimers with carboxyl terminal ends touching (cystine residues creating disulfide bonds)
- this NC2 domain is cleaved by BP1 during creation of the anchoring fibrils
NC1 domains(amino terminal) interacts with Laminin-332 and Collagen IV
Function: loops around dermal collagen
Which autoimmune subepidermal blistering diseases show dermal positioning of collagen IV/PAS staining of the blister using anti-collagen IV IHC or IF or PAS staining (patient’s biopsy sections)?
BP, PG, JEBA
