Extracellular Matrix Flashcards by Jekaterina Zeddam

What is the ECM?

Complex network of proteins and carbohydrates
—> filling spaces between cells

Both fibrillar and non fibrillar components

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What are the key functions oft he ECM?

Provide physical support

Determines mechanicals and physio chemical properties of tissue

Influence growth, adhesion and differentiation statuts of cells and tissues

Essential for development, tissue function and organogenesis

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What is the connective tissue?

ECM + component cells

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What are the components of connective tissues?

Collagens

Multi-adhesive glycoproteins

Proteoglycans

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Examples a of collagens.

Type I, II, III —> fibrillar

Types IV —> non-fibrillar —> basement membrane

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Examples of multi-adhesive glycoproteins.

Fibronectin, fibrinogen

Laminins —> basement membrane

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Examples of proteoglycans.

Aggrecan, versican, decorin

Perlecan —> basement membrane

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What are the different types of connective tissue?

Tendon and skin —> tough and flexibles

Bone —> hard and dense

Cartilage —> resilient and shock-absorbing

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How do the different types of connective tissue come about?

Difference in ECM components

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What 2 things do gene mutations affect in the ECM that can cause human disorders?

ECM proteins

ECM catabolism (hoe ECM molecules are broken down)

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Examples of gene mutations affecting matrix proteins.

Osteogenesis imperfecta

Marfan’s syndrome —> fibrillin 1

Alport’s syndrome —> type IV collagen (alpha 5)

Epidermolysis Bullosa

Cognitive Muscle Dystrophy —> laminin 2 (alpha 2 chain)

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Gene mutations affecting ECM catabolism examples.

Hurler’s syndrome —> L-alpha-iduronidase

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Fibrotic disorders due to excessive ECM deposition.

Liver fibrosis —> cirrhosis

Kidney fibrosis —> diabetic nephropathy

Lung fibrosis —> idiopathic pulmonary fibrosis (IPF)

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Disorders due to excessive loss of ECM

Osteoarthritis

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What are collagens?

Family of fibrous proteins

Major proteins in bone, tendon and skin

Most abundant proteins in mammals

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What is the alignment of collagen fibres like?

Successive layers nearly at right angles
—> resist tensile force in all direction

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How many types of collagen exist in humans and how many genes encode them?

28 types

42 gene

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What is the structure of collagen?

3 alpha chains —> from triple helix

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What is the composition of Type I collagen?

[alpha1(I)]2 [alpha2(I)]

Heterotrimer

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What ois the composition of Type II and III collagen?

[alpha1(II)]3

[alpha1(III)]3

Homotrimers

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What is the structure of the triple helix?

Each chain: gly-x-y repeat —> often x proline y hydroxyproline

Chain form a left-handed helix

Three alpha chains (approx 1000 amino acids) pack together to form stiff triple helical structure

Why must every third position in a collagen triples helix alpha chain need to be glycine?

Glycine is smallest amino acid so is small enough to occupy the interior of the helices with its H side chain
—> helix can pack closely together

How are collagen fibres assembled?

1 alpha chain

3 alpha chains (helix)

Collagen fibril

Collagen fibre

What are the steps in fibrillar collagen biosynthesis?

Synthesis of pro-alpha chain
Post translational modifications
—> hydroxylation of selected prolines ans lysines
—> glycosylation of some hydroxylysines
Self-assembly of 3 pro-alpha chains into procollagen triple helix
Procollagen packed into secretory vesicle (or transferred into cytoplasm)
Secreted out of cell
End termini cleaves
Self-assembly into fibril
Aggregation of collagen fibrils to form a collagen fiber

What function do covalent cross-links in collagen have?

Provide tensile strength and stability Type and extent —> tissue specific and changes with age

Where do the covalent cross-links in collagen happen?

Lysine and hydroxy-lysine residues

Why is lysine and proline hydroxylation important?

Contributes to interchain hydrogen bond formation

What happens in Scurvy?

Vit C deficiency —> under-hydroxylated collagens —> dramatic effects on tissue stability

What does lysine and proline hydroxylation require?

Fe2+ and Vit C

What is Ehlers-Danlos syndrome (EDS)?

Inherited connective tissue disorder - fargile skin and blood vessels - hyper-mobile joints - stretchy skin - loose joints Due to mutations in collagen which affect: —> production —> structure —> processing

What are the non-fibrillar collagens?

Types IX and XII Types IV

What do types IX and XII collagen do?

Associate with fibrillar collagens —> regulate organisation of collagen fibrils

What does Type IV collagen do?

Network forming collagen —> in all basement membranes N and C termini not cleaved —> domains interact with one another to form a network

What is the basement membrane?

Flexible, thin mats of ECM underlying epithelial sheets and tubes containing collagens, glycoproteins and proteoglycans

What happens in Diabetic Nephropathy?

Accumulation of ECM —> highly thickened basement membrane —> restricts renal filtration —> renal failure

What happens in Alpert syndrome?

Mutation in collagen IV —> abnormally split and laminated GBM —> progressive loss of kidney function

What are laminins?

Heterotrimeric protein —> alpha, beta and gamma chain

What is the purpose of laminins?

Multi-adhesive protein —> interacts w/ variety of cell surface receptors —> integrin and dystroglycan Can self-associate as part of basement membrane matrix Can also interact with matrix components —> type IV collagen, nidogen and proteoglycans

What is Congenital muscular dystrophy

Absence of alpha2 chain in laminin 2 Decreases adhesion and basement membrane stability? Muscle weakness and degeneration

What are elastic fibres made up of?

Ealastin core and surrounded by microfibrils rich in protein fibrillin Woven to limit the extent of stretching

What is the function of elastic fibres?

Provide elasticity to tissues

What is fibrillin important for?

The integrity of elastic fibres

What is Marfan’s syndrome?

Mutation in the fibrillin-1 protein Aberrant thickening of the aortic worth fragmentation and disarray of elastic fibres —> can be predisposed to aortic ruptures

What is elastin?

Small protein arranged in a random coil of alternating hydrophobic and hydrophilic domains Lysine residues cross linked during formation of mature elastin

What are fibronectins?

Dimmer with many diff domains —> disulphide link at C terminal Derived from a single gene —> alternate splicing of mRNAs give rise to different types —> insoluble fibrillar matrix —> soluble plasma protein

What is the function of fibronectins?

Regulate: - cell adhesion - migration in embryogenesis - tissue repair Important for: - wound healing - helping promote blood clotting Bind multiple ligand and cell receptors

What are proteoglycans?

Core proteins w/ covalently attached glycosaminoglycan (GAG) chains

What are GAG chains made up of?

Repeating disaccharide units w/ 1 or 2 sugars being an amino sugar Sulfation/craboxylation can increase negative charge

What are the main GAG varieties?

Hyaluronan Chondroitin sulfate/Fermat an sulfate Heparan sulfate Keratan sulfate

What is hyaluronan?

Carbohydrate chain w/out a core protein Unsulfated Found in highly viscous tissue Key role in protecting the cartilaginous surface from damage

What is aggrecan?

Major constituent of cartilage Perfectly suited to resist compressive forces —> water given up but regained once load is reduced

What does Osteoarthritis do?

Erosive disease resulting in loss of ECM vis degradation Cushioning properties of cartilage over bone ends is lost —> aggrecan cleavage by aggrecan AES’s and metalloproteinases