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MCB 1 Block 3 > ECM > Flashcards

ECM Flashcards

1
Q

ECM organisation Fibers

A

embedded in proteoglycan gel
Collagen (str, resists stretch and orgo ECM)
Elastin (elasticity) - fibrillin

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2
Q

ECM organisation Ground Substance

A

Hydrated gel, resists compression, permits rapid diffusion of nutrients, metabolites, Hormones between blood and tissue
Proteoglycans (protein and GAGs): resist comp and fill
Glycoproteins (sugars and prot): Adhesive = fibronectin, laminin, entactin

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3
Q

ECM determination of physical properties of tissue

A

Components secreted locally, assembled into meshwork with cell producing them (fibroblasts)

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4
Q

Function of ECM

A
  1. Scaffold to stabalize physical structure and resist forces
  2. Influence cell behavior, survival, development, migration, proliferation, shape, and function
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5
Q

Influence of ECM on structures

A

Bone/teeth (calcified), Corneal Stroma (transparent), tendons (ropelike), Cartilage (shock absorb)

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6
Q

Functions of fibrous proteins

A
  1. Fibrous proteins impart str and flex
  2. Simple repeat element of 2nd struc
  3. Water insoluble (Hphobic, packed center)
  4. EC, long lived proteins
  5. Construct CT, tendons, bone, matrix
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7
Q

Collagen general info

A

3x helix of alpha chains for tensile strength of tissue.
Components of tendons (increased tensile str, parallel bundles) skin (loose, flexible fibers) teeth/bone (contains hydroxyapoptic-Ca phosphate polymer), Cornea (nearly crystalline, transparent)
Made by fibroblasts (osteoblasts, chondroblasts) and epithelial cells (BL)

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8
Q

Collagen AA’s

A

Glycine every 3rd AA allows H bond between gly backbone with adjacent helix
Proline and hydroxyproline (25%) = kinks, fixed angles, helps helix formation
Lysines and hydroxylysines

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9
Q

Collagen organisation

A

3x helix = str - resists unwinding
Formed as long preprocollagen
Type 1 collagen: 2x alpha1 chains and 1xalpha2 chain. Prepro - sig seq - rER=formation - cleaves sig seq - procollagen= peptide domains enter helix formation and prevent premature fibril formation

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10
Q

Procoll processing in ER

A

Hydroxylation of prolyl and lysyl residues; important for interchain H-bonds. Glycosylation of H-lysins
Disulfide bond form (C term); aligns chain, intiates 3x helix form - zip C’ to N’’
H-bonds btwn 3 procoll - procoll 3x helix - golgi - secreted

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11
Q

Proline and lysine: post transL in ER

A

to hydroxy form (rqr ascorbic acid;vit C; and iron) hydroxyproline only in collagen (and elastin)
Lack H-proline destabilizes 3x helix
Hlysine - intra and intermolec collagen (crosslinking= site for sugar attachment and stable crosslink form)
Hproline= helix stability w/o = destab at >20 deg C

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12
Q

Post secretion Collagen fibril form

A

Peptidases remain N+C peptides: proc - coll= additional crosslinking
Self assembly to coll fibrils: fibril cross link by lysine mod, inter and intra molec crosslinks increase strength of collagen fiber

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13
Q

Covalent Intramolec and inter bonds btwn Lys and H-lys

A

Lys and Hlys deanimated by lysyl oxidase (ec) - reactive aldehyde (needs o2 and cooper)
Aldehydes react spontaneously to covalent bonds with each other or other lys/Hlys (usually at ends, stab side by side packing)

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14
Q

Collagen families

A
  1. Fibrillar - 1,2,3,4
  2. Fibrillar Associated (FACIT=connecting collagen): 6,9,12
  3. Sheet (network) forming coll: 4,10
  4. Anchoring fibrils: 7
    * 6 bonds and link type 1 fibrils
    * 9 bonds and links type 2 fibrils and bind chondrotin sulfide (GAG)
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15
Q

FACIT

A

Fibril associated Collagen (6,9,12) with interrupted triple helices
Organize fibrils in ECM: mediate interaction of coll fibrils with other fibrils and ECM proteins, proteoglycans, GAGs

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16
Q

FACIT Binding fibrillar coll surface

A

3 stranded structure interrupted by non-helical domains to increase flex than fibrillar coll. Retains propetides after secretion therefore ends not cleaved

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17
Q

FACIT binding fibrillar coll locations

A

Different fiber organization:
Tendons - org into parallel bundles along major axis of tension
Corneal Stroma: perpendicular angles

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18
Q

Degradation of Collagen: Matrix Metalloproteinases (MMPs)

A

MMP1 (coll1) MMP (coll4) remodel ECM
Zn dependent enzymes - degrade ECM: secreted as zymogen, function following activation by other proteins, increased MMP activation = cancer invasion and metastasis

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19
Q

Elastic Fibrils ECM provide Elasticity

A

Elastin = dom ECM protein in arts, skin, lungs, uterus, highly H-phobic, rich proline and glycine (not glycosylated and no H-lys)
Collagen often interwoven to limit stretch and prevent tearing

20
Q

Elastic Fibril formation

A

Soluble tropoelastin secreted and assembled into elastic fibers close to PM = little 2nd struc (stretch). Covalently crosslinked to form fiber and sheet (tropo to elastin)

21
Q

EF consists of Elastin microfibrils

A

Elastin core covered with microfibrils, composed of glycoproteins (fibrillin)
Fibrillin binds to elastin for assembly and integrity of EF
Microfibrils = scaffold for deposited elastin

22
Q

Elastic Degradation

A

Elastase= serine proteases, secreted by neutrophils (increased flex= inhibit elastin)
alpha1-antitrypsin (a1-AT) binds to active site on elastase and trypsin (secreted by liver)

23
Q

Glycasamoglycan (GAG) and proteoglycans

A

GAGs covalently linked to core protein to form proteoglycan = very long unbranched negative charged repeating disaccs. Amino sugar (NAcylglu/Nacyl galac::: usually sulfated) Sugar acid (glucuronic/iduronic). Neg charge attracts Na and therefore water

24
Q

Hyaluronic- unique GAGs

A

Repeat around 25k nonsulfated disaccs (GLCNAc-Glucorunic Acid), not covalently bound to core protien, synth by enzyme on basal epi surface and intracell to be secreted

25
Q

Function of Hyal GAGs

A

Produced during wound healing to cell free space allowing easy cell migration
Lubes joints (attracts H2O)
Resists compression
Backbone for large proteoglycan complexes (Aggrecan)

26
Q

Hyal in eye (Vitrous humor)

A

Noncompress, increased viscoelasticity
Struc: proteoglycans cross link coll fibrils (2,9) via specific binding sites on coll fibrils. Proteogly-coll structure held by Hyal network

27
Q

Proteoglycan Structure

A

Sugar groups to core protein = large complexes with Hyal

28
Q

Aggrecan Proteoglycan in cartilage

A

Hyal acid forms central core but not covalent bound to proteins. Core proteins associated with Hyal Acid through link proteins

29
Q

Functions of Proteoglycans in ECM

A
  1. Forms porous hydrated gel - fills spaces and resists compression
  2. Structural - associated with each other, coll and basal lamina
  3. Cell signaling - binds growth factors, increases cell surface receptor binding affinity for growth factors
  4. Cell migration - free space, bind and regulate of proteases and inhibitors, immobilize chemokines
30
Q

Basal Lamina

A

Specialized ECM, flexible, thin. Underlies epi, surrounds individual cells, skl muscle cells, adipocytes, schwann cells. Interposed between 2 cell sheets (kid glom)

31
Q

Basal Lamina Network

A

Produced by adjacent cells: Type 4 collagen (sheer formation), Laminin, entactin/Nidogen, HSPGs = Perlecan

32
Q

Adhesive glycoprotein: Laminin

A

Anchors epi cells to BL: Laminin and type 4 coll bind = scaffold, also binds HSPG, entactin, integrins
Org assembly of BL by binding cell membrane laminin receptors (integrins, dystroglycans)
Laminin receptor binding (adhesion) increases cell growth and differentiation
Most prevalent constituent of all Basal Lamina

33
Q

Perlecan Function in BL

A

(Heparin Sulphate proteoglycan, HSPG) is found in all cell BM. Mediates cell attachment to BL for endothelial cells and fibroblasts:
Binds enactin, laminin, coll 4 and fibronectin. Interactions with other proteoglycans in matrix increase strength

34
Q

ECM proteoglycans bind to Mitogens

A

HSPGs perlecan and Syndecin function in angiogenesis and mitogenesis. Perl and Syn bind and sequester Growth factors - bind to R on cell surface with increased affinity

35
Q

GAGs function as charge and size filter

A

HSPG perlecan rich in BL of kid glom, prevents macromolec passing to urine
GAGs=size and charge filer as most proteins are neg charge similar to GAG
Diabetes induced changes in renal BM changes renal selectivity

36
Q

BL functions

A
  1. Structural support for cells (transmembrane integrin receptor bind coll 4 and laminin= organizes cells and tissue)
  2. Scaffold for tissue regen
  3. Filter in glom, selective barriers
  4. Determines cell polarity
  5. Cell survival, proliferation, differentiation
37
Q

Fibronectin

A

Org ECM and cell attachment: all ECM (except coll 4, BL, mod’d by laminin), as a Dimer

  1. Binding site for ECM components: Coll (fibrillar), proteoglycans, fibrin
  2. Binding site for cell surface receptors (integrins): RGD (Arg, Gly, Asp) sequences
  3. Soluble plasma fibronectin = plasma glycoprotein, made by liver, circulates in blood, enchances blood clot
  4. Insoluble on cell surface and deposited in ECM
    * Necessary for embryogenesis as it guides cell migration
38
Q

Fibronectin secretion

A

Secreted by fibroblasts: fibronectin dimers crosslink and assemble into fibrils by binding to integrins at cell surface - stims fibril formation with other fibronectins via disulfide bonds

39
Q

Deficiency of Vit C (Asorbic Acid)

A

Scurvy - fewer coll bonds formed, weak CT, def for 20-40 days, bleeding gums, loose teeth, eccymoses, poor wound healing, bone develop anemia and fatigue
Risk in elderly, alch, smokers, lost through cooking

40
Q

Ehlers Darlos Syndrome

A

Defect in coll (fibrillar) synth - improper assembly of coll therefore CT weak leading to hyperextensible skin and joints

41
Q

Collagen Defects: Disorders

A 
Coll Mutation - CT defects
Osteogenesis imperfecta: 1
Ehlers Dalos: 1,3,5
Alport Syndrome: 4
Good posture syn: 4
Epidemolysis Bullosa: 7
42
Q

Marfan Syndrome

A

Fibrillin gene mutation - weak elastic tissue, Heart (aortic root dilation, dissection, aortic/mitril regurgitation) Eye (lens subflexion, retina detach) Skeleton (tall thin, arachnodactyly and pectus involvement)

43
Q

Defect in a1-AT

A

Uninhib destruction of elastic fibers by elastase

COPD (emphysema) - AR, by 30-50, early=smoking

44
Q

Destruction of alveolar tissue by neutrophil elastase

A

Smoke = irritant and inhib a1-AT (oxidizes Methionine) so smoking recruits neutrophiles which release elastase leading to lung (paranchymal) tissue non regen - elastic loss - decreased flex of alveolus - stagnant alveolar air, resp insufficiency, resp distress
Tx=a1-AT

45
Q

Diabetic Nephropathy: BM dysfx

A

HSPGs detect sieving properties and inhibit uncontrolled replication of cells on BM
Hyperglycemia - decreased HSPG, coll glycosylation, crosslinking - GBM thickening due to increased coll and decreased HSPG - expansion of mesangial matrix leading to kidney failure (#1 cause)

MCB 1 Block 3 (18 decks)

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