9.6.16 Lecture Flashcards
What are the two main ways animal cells are bound together?
Connective tissue and epithelial tissue
Compare epithelial tissue and connective tissue (4 major categories).
- Epithelial - scanty ECM, Connective - plentiful ECM
- Epithelial - many cells, Connective - sparse cell distribution
- Epithelial - cells tightly bound together in sheets, Connective - matrix rich in fibrous polymers
- Epithelial - cells bear most of mechanical stress through junctional complexes attached to the cytoskeleton, Connective - matrix bears mechanical stress
Long-term connections between cells require complex ___.
Cell junctions
What are the 4 major types of connections between cells? Briefly describe their function.
- Anchoring junctions - link cells to cells (via TM cadherins) or cells to matrices (via TM integrins)
- Occluding/tight junctions - seal gaps between epithelial cells (involve claudins)
- Channel-forming junctions - form passageways for small molecules and ions to pass from cell to cell (involve connexins)
- Signal-relaying junctions - complex structures that typically involve anchorage proteins alongside proteins mediating signal transduction.
What are the three functions of occluding/tight junctions?
- Seal cells together to create a permeability barrier
- Regulate paracellular transport
- Fence function that separates the apical and basolateral membrane domains, keeping membrane proteins and lipids in the appropriate domains
Provide 3 examples of the use of occluding junctions to seal cells together.
- Intestinal epithelium use occluding junctions for transcellular glucose transport.
- Endothelial cells use occluding junctions to prevent plasma leakage from the blood vessels
- Brain endothelial cells use occluding junctions to form the blood-brain barrier.
What is paracellular transport?
Leakage of materials between cells (rather than through cells)
Describe the general process of transcellular glucose transport.
The apical surface of the cell (lumen of the gut) has a high glucose concentration. The sodium/glucose symporter transports glucose into the cell, which also has a high glucose concentration. Then, the glucose flows out of the cell into the blood on the basolateral surface, down its concentration gradient.
What is the main occluding protein and how many membrane passes does it make?
Claudin; 4
What are the 2 functions of anchoring junctions?
- Stabilize cells against mechanical stress/transmit force
2. Mechanically attach cells and their cytoskeletons to their neighbors or to the ECM.
What are the 2 broad categories of anchoring junctions?
- Cell-cell
2. Cell-matrix
What are the 2 types of cell-cell anchoring junctions?
- Adherins junctions
2. Desmosomes
What are the 2 types of cell-matrix anchoring junctions?
- Focal contacts (actin-linked cell-matrix junctions)
2. Hemidesmosomes
What is the adhesion protein of adherens junctions? What extracellular ligand to these bind to? Finally, what is the intracellular cytoskeletal attachment?
Adhesion protein: classical cadherin
Extracellular ligand: classical cadherin on neighboring cell
Intracellular cytoskeletal attachment: actin
What is the adhesion protein of desmosomes? What extracellular ligand to these bind to? Finally, what is the intracellular cytoskeletal attachment?
Adhesion protein: non-classical cadherin
Extracellular ligand: non-classical cadherin on neighboring cell
Intracellular cytoskeletal attachment: intermediate filament
What is the adhesion protein of focal contacts? What extracellular ligand to these bind to? Finally, what is the intracellular cytoskeletal attachment?
Adhesion protein: integrin
Extracellular ligand: extracellular matrix proteins
Intracellular cytoskeletal attachment: actin
What are the adhesion proteins of hemidesmosome? What extracellular ligand to these bind to? Finally, what is the intracellular cytoskeletal attachment?
Adhesion proteins: alpha6beta4 integrin, type XVII collagen
Extracellular ligand: extracellular matrix proteins
Intracellular cytoskeletal attachment: intermediate filament
Adherens junctions form an adhesive belt just below ___ junctions.
Tight
Adherens junctions join an ___ bundle in one cell to that of another cell.
Actin
What are cadherins?
Calcium-dependent TM adhesion molecules that mediate homotypic adhesion; they are dimers.
What is the adaptor/anchor protein for cadherins and what do they do?
Catenins; connect cadherins to actin
Desmosomes form ___ that anchor cells together via intermediate filaments.
Spot welds
What are the two types of desmosomal cadherins?
Desmogleins and desmocollins
Desmosomal cadherins mediate cell-cell ___ adhesion.
Homotypic
What are the adaptor/anchor proteins connecting desmosomal cadherins to the intermediate filaments?
Plakoglobin and desmoplakin
What is pemphigus?
An autoimmune disease where auto-antibodies against desmosomal cadherins cause loss of cell-cell adhesion and blistering.
What are tonofilaments?
Bundles of cytokeratin intermediate filaments
What do focal contacts/focal adhesions do?
Link ECM to actin filaments so that cells can “hang on” to their surroundings
What are integrins?
TM ECM-binding proteins that bind to actin indirectly via adaptor/anchor proteins
What are the adaptor/anchor proteins of integrins and what do they do?
Alpha-actinin, talin, filamin; link integrins to actin
Describe the structure of integrins.
Formed of an alpha and beta subunit; the beta chain is link to the actin, both alpha and beta chains are linked to the ECM protein.
What do hemidesmosomes do?
Distribute sheer forces on an epithelium to the basal lamina
What are the transmembrane proteins that bind and mediate basal lamina adhesion?
Integrins
Calcium binds ___ repeats in the extracellular domain hinge regions to stabilize the structure.
Cadherin
Cadherins are ___ pass transmembrane proteins.
Single
What are the 4 members of the cadherin family and where are they found?
- E cadherin (epithelial)
- N cadherin (neurons, heart, fibroblasts, skeletal muscle)
- P cahderin (placenta, epidermis, breast epithelium)
- VE cadherin (vascular endothelium)
Cadherins are responsible for cell sorting, which is important for development. What property of cadherins allows for this?
Homophilic binding
___ and ___ mediate transient cell-cell adhesion in the bloodstream.
Selectins; integrins
Selectins are ___, which are ___-binding proteins.
Lectins; carbohydrate
Selectins are ___ and cooperate with integrins.
Heterotypic
E selectin is activated in ___ cells.
Endothelial
White blood cells bind weakly (___-dependent) or strongly (___-dependent), leading to rolling along the endothelial cells or sticking, respectively.
Selectin; integrin
What are the 4 functions of gap junctions?
- Electrically connect cells because ions can flow through them
- Metabolically couple cells by averaging small molecules throughout the tissues.
- Allows specialized cells to uncouple from cells with different fates
- Allows small molecules (ions, mono/di sugars, nucleotides) to pass between interacting cells
What are the individual proteins that constitute gap junctions and how many passes do they make through the membrane?
Connexins; 4
How many connexins form a connexon, the functional pore?
6
Gap junction permeability varies with ___.
Connexin composition
What is an example of a signal-relaying junction?
The synapse between the axon and dendrite
___ proteins organize adhesive proteins, ion channels, receptors, and more at signal-relaying junctions.
Scaffold
What is the ECM?
Hydrated gelatinous network of protein- and carbohydrate-containing molecules such as glycosaminoglycans, proteglycans, and fibrous proteins
The ECM is abundant in ___ tissue.
Connective
The ECM is secreted by what 4 cells?
Fibroblasts, chondroblasts (cartilage), osteoblasts (bone), and epithelium (basal lamina)
What are glycosaminoglycans (GAGs)?
Very long, unbranched polysaccharide chains composed of repeating disaccharide units; they are stiff, absorb large amounts of water, and occupy space
Describe the makeup of GAGs.
One sugar is always an amino sugar, usually sulfated, which gives it a negative charge and leads to attraction of salt and water. The other sugar is usually a uronic acid.
What is the simplest GAG, made of up to 25,000 disulfide units?
Hyaluronan (hyaluronic acid or hyaluronate)
Hyaluronan has no ___ sugars and is not attached to a ___. It is synthesized at the plasma membrane ___.
Sulfated; protein; extracellularly/from basal side of epithelial sheet
What is the role of Hyaluronan?
Resist compressive forces in joints and tissues, fill space into which cells can migrate (important for embryogenesis), degraded by hyaluronidase to allow for wound healing.
What are proteoglycans?
A core protein with many covalently-attached GAGs
Where are GAGs attached to a core protein to form a proteoglycan?
Golgi
How to proteoglycans differ from glycoproteins?
Proteoglycans: at least 1 side chain is a GAG, very high carbon composition by weight, long unbranched side chains
Glycoproteins: very low carbohydrate content, short, branched chains
What are the two functions of proteoglycans?
- Form specialized gels to regulate movement of molecules and cells
- Chemical signaling between cells (bind growth factors, protease, protease inhibitors)
What is collagen?
Major and must abundant ECM protein, responsible for ECM strength
Collagens make up ___% of total protein mass in mammals.
25
Describe the structure of collagen.
Long, stiff triple helix of alpha chains, each about 1,000 amino acids long; filled with repeating sequences of Gly-X-Y, where X = Pro, Y = hydroxyproline; hydroxyproline and hydroxylysine form interchain H-bonds to stabilize the triple helix, and lysine aldehydes form covalent intramolecular and inter-fibril cross-links.
Vitamin C deficiency leads to ___. How?
Scurvy; inhibition of hydroxylation and destabilization of collagen triple helices
How is collagen synthesized?
- Procollagen is secreted (propeptide prevents formation of long polymers)
- Propeptides are cleaved, forming the collagen molecule
- Collagen molecules self-assemble into a fibril
- Fibrils aggregate to form a collagen fiber
What are the 5 broad types of collagen?
- Fibril-forming
- Fibril-associated
- Network-forming
- TM
- Proteoglycan core protein
42 genes for collage alpha chains form ~___ types of collagen.
40
What are two genetic collagen disorders? Describe them.
- Osteogenesis imperfecta - defect in type 1 collagen leads to decreased synthesis, mutations, and rearrangements; autosomal dominant; leads to bone fractures and skeletal abnormalities.
- Ehlers-Danlos syndrome - mutations in genes encoding types I, II, V lead to decreased collagen hydroxylation and production; autosomal dominant; leads to skin hyperextensibility, joint dislocation, hypermobility, and vessel weakness
What is elastin?
Protein that imparts elasticity and flexibility to tissues
What causes the super rubber band-like property of elastin?
Kinked and cross-linked structure (can be stretched or relaxed)
Elastin is a major ECM component of ___.
Arteries
What are elastic fibers?
Elastin covered in fibrillin (microfibrils)
A mutation in fibrillin causes ___ syndrome. Describe.
Marfan’s; autosomal dominant, leads to excessive growth of long bones (tall stature), weakened blood vessels and heart valves (aortic dilation and rupture), and malformed cartilage and ligaments (skeletal abnormalities)
What is fibronectin?
Adhesive ECM glycoprotein that binds cells to the ECM and guides cell migration during development
Describe the structure of fibronectin.
Dimer composed of 2 large subunits joined by a disulfide bond; Arg-Gly-Asp (RGD) sequence binds integrins
What are the 2 functions of fibronectin?
- Cell adhesion to ECM via integrins/RGD interaction
2. Directs cell migration along fibronectin during development
What is the basal lamina?
Thin, flexible mats of ECM that underlie all epithelial cell sheets and tubes, and surround fat, muscle, and Schwann cells.
What are the 5 functions of the basal lamina?
- Molecular filter (kidney glomerulus)
- Orient/polarize cells (fibronectin fibrils and cytoskeleton)
- Cell migration (NMJ)
- Barrier to cell migration (cancer)
- Cell survival
The basal lamina is composed of what 6 things?
- Laminin
- Fibronectin
- Type IV collagen
- Perkcan (proteoglycan)
- Nidogen (glycoprotein)
- Heparin Sulfate (glycosaminoglycan)
What is laminin?
Major adhesive protein found in the basil lamina that binds cells, collagen, GAGs, PGs
Integrins are ECM receptors for what three things?
Laminin, fibronectin, collagen
Integrins have a low ___ but a high ___.
Affinity; copy number
Binding to integrin is ___ or ___ dependent.
Calcium; magneisum
Integrins have overlapping ___.
Specificity (8 integrins bind fibronectin, 5 integrins bind laminin)
Describe the two types of activity regulation of integrins.
- Inside-out signaling: inactive integrins are activated by cells
- Outside-in signaling: integrin binds to the ECM and activates intracellular signaling
Give two examples of inside-out signaling.
- Platelets activate beta3 integrin to bind fibrinogen and cause aggregation.
- T lymphocytes activate beta2 integrin to bind antigen presenting cells
___ of integrins at the ECM contact sites activates signaling.
Clustering
___ is recruited and activated in outside-in signaling.
Focal Adhesion Kinase (FAK)
