cell junctions

Gap junctions structure

Connexons/hemichannels - made of connexins

6 connexins make up a connexon

Connexons from neighbouring cells dock to form gap junction (channel opens only when correct docking has occurred)

Gap junctions formation

Connexins synthesised in rER

Connexins oligomerise in Golgi apparatus to form Connexons

Connexons are trafficked to the plasma membrane and inserted near existing junctional complexes (bind to scaffolding protein ZO-1)

Multiple channels cluster to form plaques

Tight junctions general

Cell-cell adhesion complexes near apical membrane

Selective barrier controls paracellular pathway and maintains cell polarity

Branching network of sealing strands - more strands = more effective at controlling permeability

40+ proteins

Tight junctions transmembrane proteins

Occludin

Junctional adhesion molecules (JAMs)

Claudins

Occludin

Tight junctions

4 transmembrane domains

Important for stability and integrity

Contributes to tightness not permeability

Junctional adhesion molecules (JAMs)

Tight junctions

Transmembrane proteins in Ig superfamily

Mediate cell-cell adhesion

Organise assembly

Interact with cytoskeleton and signalling proteins and scaffolding proteins

Claudins

Tight junctions

Determine permeability

Transmembrane proteins with 4 transmembrane domains Important

Act as selective channels

23 genes for isoforms, each allows or restricts particular ions or molecules - Claudin-1 blocks most ions and water, claudin-2 selective permeability to Na+, K+, Ca2+, water

Tight junction scaffolding proteins

Link tight junctions to actin cytoskeleton

Includes ZO-1, 2 and 3

Tight junctions formation

Formation initiated by adherens junctions

Recruitment of polarity proteins

Claudins and occludins inserted into apical lateral membrane

JAMs dimerise and stabilise cell-cell contact

ZO-1 binds to f-actin

Forms a continuous circumferential belt

Tight junctions dyfunction

Inflammatory bowel disease - reduced claudin 1 and 2, increased claudin 3 = leaky barrier

Loss of claudin 4 and 7 and occludins - linked to invasive and metastatic GI cancers

Claudin 16 and 19 mutations - impaired reabsorption of Mg2+ and Ca2+

Salmonella - effector proteins disrupt tight junctions and allow bacterial invasion

Adherens junctions - general

Belt-like adhesion complexes basal to tight junctions (strong)

Mechanical adhesions - tensile strength

Drives cell shape changes and tissue remodelling

Involved in signalling and establishing cell polarity

Adherens junctions proteins

Transmembrane = E-cadherins - form dimmers with neighbouring cells dock, calcium dependant binding

Intracellular = catenins - link cadherins to actin cytoskeleton, involved in regulating junction stability and signalling

Adherens junctions formation

Cadherins on adjacent cells form homodimers (calcium dependant)

Cadherin cytoplasmic tails recruit catenins

Catenins connect to actin

Junctions form a continuous circumferential belt

Adherens junctions dysfunction

E-cadherins essential for intestinal epithelial integrity - mutation or loss = increased intestinal permeability

E-cadherins encoded by CDH1 gene - mutations linked to ovarian, breath, thyroid, colorectal and gastric cancers e.g. hereditary diffuse gastric cancers

Desmosomes - general

Mucula adherens

Spot-like intercellular junctions

Link to cytokeratin

Strong mechanical adhesion

Abundant where high mechanical/shearing force

Desmosomes general structure

Desmosomal intermediate filament complex (DIFC)

Transmembrane proteins

Intracellular proteins

Desmosomal intermediate filament complex

Extracellular core with dense plaques

Desmosomes transmembrane proteins

Desmosomal cadherins

Desmogleins and desmocollins

Desmosomes Intracellular proteins

Plakoglobin and desmoplakin

Connect transmembrane proteins to intermediate filaments

Desmosomes formation

Desmogleins and desmocollins on adjacent cells bind

Cytoplasmic tails recruit plakoglobin

Plakoglobin binds to desmoplakin

Desmoplakin connects to cytokeratin

hemidesmosomes - general

Anchor epithelia to basement membrane

Transmembrane protein is integrity

Intracellular protein is pectin

Extracellular protein is laminin (lamina Lucida)

Hemidesmosomes formation

Integrin heterodimers inserted into basal membrane

Binds laminin - binds to basal lamina components

Integrin binds to plectin - links Integrin to keratin

Hemidesmosomes cluster to form dense adhesion sites

Focal adhesions general

Highly dynamic multi protein complexes

Mediate attachment of cell to ECM, connect to actin

More plastic than Hemidesmosomes

Involved in cell signalling and migration

Focal adhesions structure and formation

Transmembrane protein - integrins

Adaptor proteins - e.g. talins

Focal adhesion kinase (FAK) regulates adhesion turnover

Focal adhesions formation

Integrins bind to ECM components (fibronectin, collagen)

Recruitment of adaptor proteins

Link to actin

Cell junction complex formation

Early assembly required for correct positioning and development of apical polarity complexes

1. Initial cell-cell contact

2. Adherens junctions assemble (E cadherins clustering, actin remodelling, polarity initiated)

3. Tight junction formation (recruitment and positioning of polarity determining complexes (act as molecular landmarks, includes recruitment of ZO-1)

4. Desmosome formation

5. Hemidesmosomes and focal adhesions form

Gap junctions form after adherens and tight junctons, as needed