Lecture 24: The Extracellular Matrix Flashcards Preview

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Flashcards in Lecture 24: The Extracellular Matrix Deck (52):
1

General structure

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The basal lamina

• 40-120 nm mat of extracellular matrix that underlies all epithelial sheets, also called the basement membrane 

• Serve structural and organization roles 

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4 components of basal lamina

• Composed mainly of fiberous proteins and glycosyaminoglycans 

– Type IV collagen  

– Laminin 

– Nodulin 

– Perlecan (Heparan sulfate proteoglycan) 

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Type IV collagen

• Similar to type IX collagen in that it is much more flexible than fibrillar collagen due to breaks in the helical structure 

• Pro-sequences are not removed and these terminal domains help form sheetlike multilayered networks

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Functions of the basal lamina

structure, organization, filtration

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Comparative size of major ECM components 

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The structure of laminin

α-chains contain the “RGD” sequence that interacts with integrins

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Model for basal lamina organization

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Function: filtration

– The basal lamina in kidneys serve as an additional filter preventing the passage a macromolecules from the blood into the urine 

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Function: boundary formation

– Physically separates epithelial cells from underlying fibroblasts 

– Template for tissue reformation following injury 

• While the cell surrounded by the basal lamina may die, the basal lamina helps as a placeholder until new cells are regenerated. This the particularly import for muscle cells 

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Basal lamina at the neuromuscular junction

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Integrins

• Integral membrane proteins that link the cytoskeleton to the extracellular matrix 

• Can signal bidirectionally 

• Transmembrane heterodimers

• Can form transient structure like focal adhesions or stable, llong lived structures like myotendinous junctions 

• Capable of switching between active and inactive conformations 

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____ link to the actin cytoskeleton though fibronectin in the ECM and talin and vinculin as intracellular anchor protein (Focal adhesions) 

integrins

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Integrins link to intermediate filament through ____ in the ECM and ____ and ____ as intracellular anchor protein (hemidesmosomes) 

laminin in the ECM and plectin and dystonin as intracellular anchor protein

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Integrin link to the actin cytoskeleton 

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Hemidesmosome

Integrin links to intermediate filaments 

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Integrins are activated through outside in signaling

Ligand binding induces a large conformational change in the extracellular domain, resulting in strong ligand binding. This change also triggers a lateral movement of the TMD apart that generates a strong talin binding site inside the membrane. This is “outside-in” signaling. The reverse “inside-out” signaling also occurs. 

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Crosstalk from other signaling pathways can activate integrins, example of inside out signalling

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Defects in integrins result in:

skin, muscle, blood disorders, or severe complications that lead to death of embryo

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Focal Adhesions

• Connect actin filaments to the basal lamina 

• Transmembrane adhesion proteins belong to the integrin family 

• Regulated assemblies that are altered during cellular movement 

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____ regulates the number and stability of focal adhesions 

Focal Adhesion Kinase (FAK)

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Where is the extracellular matrix in this picture?

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blue part

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Primary ECM components 

• Polysaccharide chains 

– Glycosaminoglycans (GAGs) 

– Proteoglycans 

• Fibrous proteins 

– Collagen 

– Elastin 

– Fibronectin 

– laminin 

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Fibroblasts in connective tissue are mainly made up of: 

Mainly collagen fibrils, no elastic fibers, glycoproteins, hylauronan, or proteoglycan that are normally present

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Glycosaminoglycans (GAGs) 

• Unbranched polysaccharide chains composed of repeating disaccharide units 

• All GAGs contain an amino sugar (Nacetylglucosamine or N-acetyl galactosamine) and a uronic acid (iduonic acid or glucuronic acid) 

• Occupy a large amount of space 

• Form hydrated gels 

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Four main groups of GAGs

– Hyaluronan 

– Dermatan sulfate and chondroitin sulfate 

– Heparan sulfate 

– Keratan sulfate 

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Repeat unit of a Heparan sulfate glycoaminoglycan (GAG) chain 

Typically 70-200 sugars long. Shown fully sulfated. In vivo, the proportion of sulfated and non-sulfated is variable Heparin typically has >70% sulfate while heparan has <50%

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Relative dimensions and volumes of various macromolecules 

• The stiffness of polysaccharides prevent them from folding into compact structures like proteins 

• Their charge can also attract counter ions, primarily Na+, causing large amounts of water to flow into them 

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Hyaluronan 

• Also called hyaluronic acid or hyaluronate

• Simple GAG of repeating disaccharide units up to 25,000 sugars long

• Important lubricant in joints 

 

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How is hyaluronan different from other GAGs

 • Unlike most other GAG, it does not contain sulfated sugars 

• Not linked to a protein cores 

• Not secreted like other GAGs, but is synthesized at the inner face of the plasma membrane and extruded out of the cell 

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Repeat unit of hyaluronan, a simple glycoaminoglycan (GAG) 

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GAG linkage to core protein in a proteoglycan 

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glycoprotein

– 1-60% carbohydrate by weight 

– Numerous, short, branched oligosaccharides 

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proteoglycan

– Up to 95% carbohydrate by weight 

– Mostly long, unbranched GAG chains (typically 80 sugars) 

– Can be enormous in size 

• Aggrecan ~ 3 megadaltons (3x106) with over 100 GAG chains 

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What are examples of small and large proteoglycans

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Aggrecan aggregate 

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Proteoglycan functions

• Proteoglycans can regulate the activities of secreted factors 

• Proteoglycans and their GAG chain can form porous gels of varying charge and spacing to restrict or facilitate passage of certain molecules 

• Proteoglycans bind to and regulate the activity of certain growth factors

• Cell surface proteoglycans can act as co-receptors

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Proteoglycans can regulate the activities of secreted factors

– Immobilize a protein close to its site of action 

– Sterically block the activity of a protein 

– Provide a reservoir for delayed release 

– Protect a protein from degradation, prolonging its activity 

– Alter the concentration for more effective presentation 

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Proteoglycans bind to and regulate the activity of certain growth factors 

– Fibroblast growth factor (FGF) binds to heparan sulfate portion of proteoglycans to crosslink receptors 

– Some members of the TGFβ family bind to the core protein region of a ECM proteoglycan like decorin which inhibit their activity 

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• Cell surface proteoglycans can act as co-receptors

 – Not all proteoglycans are soluble. Some have integral membrane protein cores or are GPI linked 

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Major protein components of the ECM

• Collagen 

• Elastin 

• Fibronectin 

• Laminin 

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Collagens

• Major component of skin and bone 

– Constitutes ~25% of total protein mass in mammals 

• Long, stiff, triple helical structure composed of 3 α-chains 

• 42 distinct collagen α-chain genes yielding a large degree of heterogeneity in the triple helix 

• Rich in glycine and proline which are vitally important to the collagen triple helix 

• Synthesized with N- and C-terminal prosequences that function in the assembly process 

• Forms higher order fibrils though crosslinks 

• Fibrils assemble into bundled of fibers 

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Structure of a typical collagen molecule 

X is commonly proline 

Y is commonly hydroxyproline

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Things caused by collagen defects

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Collagen contains which two modified amino acids?

These modified residues form interchain hydrogen bonds to stabilize the triple helix 

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Crosslinks in collagen fibrils 

Crosslinks occur between the modified lysine side chains mainly in the non-helical region. Crosslinks form extracellularly involving a deamination of certain lysines and hydroxylysines by lysyl oxidase. This type of crosslink also occurs in elastin.

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Production and secretion of collagen 

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Type IX collagen

• Fibril associated collagens help organize fibrils 

• These collagens usually contain a short non-helical segment that makes them more flexible 

• They retain their propeptide and do not associate into fibers 

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___ give tissues elasticity 

Elastins

Basically like spaghetti that can stretch and relax. 

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Fibronectin

• Dimer of two large subunits 

• All forms of fibronectin are encoded by a single gene with ~50 exons 

• The main module is an ~90 amino acid repeat called the type III fibronectin repeat 

• The type III fibronectin repeat contains a tripeptide sequence RGD that is recognized by members of the integrin cell adhesion receptors 

• Fibronectin exist in both soluble and fibrillar forms 

– Fibers only form on the surface of cells usually following association with a receptor like an integrin 

• Fibronectin fibers often align with intracellular actin filaments 

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Structure of fibronectin

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Unfolding of a Type III Fibronectin repeat in response to tension 

Fibronectin binding to integrins can generate tension and unfold portions of fibronectin. The newly expose portions of the the partially unfolded fibronectin allow other interactions including self oligomerization to occur