Lecture 41: The cytoskeleton and cell-cell junctions Flashcards
Tuesday 28th January 2025
What are the advantages of multicellularity?
- Multicellular organisms can exploit resources that many single celled organisms cannot.
- Even in the simplest multicellular organism, the cells co-operate.
- In a multicellular organism, cells become specialised.
- Cell interactions are crucial, allowing cells to assemble into tissues and to communicate.
How can cells combine in their millions to form large, very strong structures (e.g. animals)?
The strength comes from:
- the strength of the internal cytoskeleton
- the cell-cell adhesions that tie the cytoskeletons of neighbouring cells together
- and the extracellular matrix (ECM) (Lecture 40)
The strength of the internal cytoskeleton
The strength of the internal cytoskeleton
Describe the cytoskeleton
- Provides mechanical strength
- Drives organelle movement i.e. secretory pathway organelles move along microtubules
- Serves as an anchor for cell-cell junctions, Determines cell polarity
- Drives chromosome segregation in mitosis and splits the cell in two (cytokinesis)
- Enables cell movemen and muscle contraction
- Made up of microtubules, actin filaments, intermediate filaments
Describe microtubules function
- They position and move organelles
- They segregate chromosomes during mitosis
- Help cells undergo cytokinesis
Describe the structure of microtubules
- Stiff tubular structures made up of non-covalent heterodimers of α and β tubulin subunits.
- Both subunits bind GTP and GDP.
- There is a polarity: a (+) plus end and a minus (-) end.
- GTP-bound heterodimers bind only at the + ends: growth of a microtubule is unidirectional, from the (+) end only
Microtubules growth and shrinkage
- Microtubule growth happens from the (+) end only. This produces a GTP cap at the + end, which stops fraying.
- The rest of the GTP will be converted to GDP during growth.
- Shrinkage happens from the (+) end only and is extremely rapid if the end is bound to GDP
- Microtubules are dynamically unstable and they are restructured very rapidly
Describe the function of actin filaments
- Actin filaments can grow from both ends
- Actin molecules are more flexible than microtubules … but they can bundle together to form very strong structures
- Actin controls cell shape and cell movement
Describe the structure of actin filaments
- Actin filaments are non-covalent polymers of actin monomers
- Each monomer binds ATP (which is replaced by ADP in the filament)
- Two filaments twist around each other to form an actin molecule
- There is a polarity: a plus (+) end and a minus (-) end
Describe function of intermediate filaments
They provide mechanical strength to cells- they bend, but they do not break
Are motor proteins usually associated with the cytoskeleton?
Yes
Describe the structure of intermediate filaments
- rope-like fibres:
α-helical monomers
Intermediate filament proteins
coiled coils
filaments - large and diverse family of non-nucleotide binding proteins (e.g. nuclear lamins or epithelial keratins)
How is the cytoskeleton dynamic?
- Each cytoskeletal element is made up of several protein subunits
- Assembly and disassembly of these subunits results in growth/shrinkage of filaments and allows for rapid structural reorganisation
- These elements can also form stable structures - cell-to-cell junctions
- And these influence: cell to cell communication, cell organization, developmental choices.
What are the 2 types of cell to cell junctions invertebrates?
- Adherens junctions
- Desmosomes
Describe desmosomes
- They contain specialised cadherins that connect intermediate filaments in one cell to those in the next cell.
- They are abundant in epithelia and in tissues that are subject to high mechanical stress
Describe adherens junctions
- Adherens junctions allow indirect linkage of the actin cytoskeletons of neighbouring cells
- Contain cadherins
What allows the adherens to function?
The cadherins
Describe cadherins
- Cadherins are transmembrane proteins that form homodimers
- the extracellular polypeptides contain five cadherin domain repeats
- There are Ca2+-binding sites between each one of the repeats
- There are many members in the cadherin superfamily (180 in humans)
“Cadherins of the same type in the plasma membranes of adjacent cells will interact weakly (so each pair is easily disassembled)
However, having lots of interactions gives an overall strong attachment, a ‘Velcro’ effect.” Is this true? and what is this called?
Yes. Homophilic binding
What affects cadherin structure?
The loss of Ca2+
Is it true that adherens junctions also coordinate the actin-based motility of adjacent cells?
Yes. This is because the cadherin interactions indirectly link the actin cytoskeletons of adjacent cells via anchor/adapter proteins (e.g. catenins).
Adherens junctions connect indirectly to the actin cytoskeleton via catenins and so influence the coordinated contraction of cells (especially in the epithelial layer).
Adherens junctions connect indirectly to the actin cytoskeleton via catenins and so influence the coordinated contraction of cells (especially in the epithelial layer).
How do adherens jucnctions form a ‘belt’ around epithelial cells?
- Adherens junctions in many cells are small punctate attachment points
- But in epithelial cells they form a continuous contractile belt around the cell: multiple connections forming a transcellular network
Is it true that adhesion belts can tighten to cause invaginations/ tubulation of epithelial layers?
Yes
Adherens junctions summary
- The cell-cell interacting membrane proteins are cadherins.
- The homophilic interactions they make are weak, but many acting together makes for strong attachment points.
- Cadherins enable cells to be recognised and to be segregated and sorted. Changes in cadherin expression affect this (important in development, tissue formation, cell migration and wound repair)
- Abnormal expression of cadherins is connected to cancer metastasis, angiogenesis, adhesion and invasion.
- The junctions connect indirectly to the actin cytoskeleton via catenins and so influence the co-ordinated contraction of cells (especially in epithelial layers).
- There is a complex interplay between chemical signalling pathways (see upcoming cell cycle lectures) and cell-cell adhesion
What do focal adhesions do?
They connect the ECM to the cytoskeleton
What are integrins?
trans-membrane proteins that allow the internal cytoskeleton to grip onto molecules in the ECM when necessary.
Integrins bind to ECM molecules…
- Each integrin is a α/β heterodimer that links an ECM molecule to talin.
- Talin links to actin. Other proteins reinforce the linkage.
- Integrins: There are 8 different β chains, and 18 different α chains, each with distinct ligand binding properties (for different ECM components). Wide combinatorial repertoire!
Are integrins transmembrane proteins?
Yes
Each integrin links intracellular matric molecules to talin, which links to the actin directly. This is important because many cells need anchoring to the ECM to grow and proliferate; detached cells may even die.
Each integrin links intracellular matric molecules to talin, which links to the actin directly. This is important because many cells need anchoring to the ECM to grow and proliferate; detached cells may even die.
What is the importance of ECM interactions?
- Many cells need anchoring to the ECM to grow and proliferate
- Lack of anchoring exposes cells to stress (loss of growth stimuli, altered mechanical force, cytoskeletal reorganization, reduced nutrient uptake,…)
- Detached cells may even die if contact with ECM is lost
- This is called anchorage dependence and it is mediated by integrins and the signals they generate inside cells (these are complex pathways involving integrins and conventional signalling receptors – not covered here)
Is a type junction a type of cell junction in vertebrates?
Yes
Describe tight junctions
- Seal the gap between epithelial cells
- Maintain cell polarity- relevant to epithelial cells
- They block the mixing of apical & basolateral membrane proteins to maintain cell polarity.
What is the importance of cell polarity?
- The maintenance of cell polarity is functionally important e.g. in the gut it ensures a one-way movement of glucose from the gut lumen to blood.
- Here, inward active transport of Glucose is confined to apical surfaces while outward passive transport of Glucose is confined to the basolateral membrane because the relevant transporters are separated and cannot intermix
What do tight junctions look like?
- Thin bands of integral plasma membrane proteins (claudin and occludin) encircle the cell. Rows of such proteins from neighbouring cells interlock to form a tight extracellular seal.
- The rows of proteins also prevent lateral diffusion of lipids and proteins in the plasma membranes of the cells.
Are gap junctions a type of cell juncition in vertebrates?
Yes
Describe gap junctions
- Allows the passage of small water soluble molecules from cell to cell.
-
Describe the structure of channel forming gap junctions
Channel proteins (called connexons, that are each made up of six connexins) from adjacent plasma membranes align to create homotypic or heterotypic channels between cells
Dexcribe the roles of gap junctions
- Allow metabolic coupling, and for many cells, electrical coupling
- Smooth out any fluctuations in the concentrations of small molecules in neighbouring cells
- Help co-ordinate cell responses (e.g. in liver, where many cells must respond to a nerve signal received by only a few of them)
- Important where neurons need to act in synchrony (e.g. in the heart and gut). Cell coupling by gap junctions in such cells allows action potentials to spread rapidly, avoiding delays at synapses
Overall summary
- Multicellularity requires cells connecting to each other: this requires the cytoskeleton and the formation of cell-cell junctions
- Three major cytoskeletal elements: microtubules, actin microfilaments, intermediate filaments. these provides the internal scaffold for the formation of cell-cell junctions or cell – extracellular matrix junctions.
- Adherens junctions use cadherins to link neighbouring cells
- Focal adhesions use integrins to link cells to the ECM
- Tight junctions use claudins/occludins to maintain cell polarity and prevent leakage between cells
- Gap junctions use connexins to form passageways between cells
- Proteins involved in cell-cell junctions are also active in intracellular signalling and developmental transitions
