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Biochemistry Muscoskeletal > ECM > Flashcards

ECM Flashcards

1
Q

How the ECM assists in the function of a multicellular organism?

A
  1. Stabilizes the physical structure of cells
  2. Molecular barrier to cell migration during infection and metastasis
  3. Provides signals to the cell interior during morphogenesis
  4. Wound healing
  5. Maintenance of the differentiated state
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2
Q

The ‘reinforcing fibers’ of the ECM?

A

Collagen

Elastin

Keratin (in hair and nails)

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3
Q

What components make up the ‘hydrated gel’ in which cells and reinforcing fibers are embedded?

A

Proteoglycans (in most tissues)

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4
Q

Role of…

  1. Fibroblasts
  2. Chondrocytes
  3. Osteoblasts
A

Synthesize ECM after…

  1. Wound healing
  2. Formation of cartilage
  3. Formation of bone
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5
Q

What ‘holds’ the cells in the ECM?

A

The multi-adhesive matrix proteins

Fibronectin, laminin, thrombospondin, entactin, etc.

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6
Q

Proteoglycan vs. glycosaminoglycan?

A

PGs = consist of one or more GAGs covalently attached to a core protein

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7
Q

Hyaluronic acid

A

And example of the fact that not all GAGs are also PGs…

Since it does not covalently attach to a protein

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8
Q

Proteoglycan aggregate in cartilage…

What happens to it during osteo-arthritis? (OA)

A

Aggrecan binds to hyaluronic acid via a link protein —> required for proper cartilage function

Proteolytic cleavage of the aggrecan core protein by matric metalliproteases (MMPs) and multidomain extracellular protease enzymes (ADAMTS) —> release the fragment carrying the GAG molecules from the PG aggregate

This loss of the GAG component —> makes the cartilage lose its self-lubricating properties —> OA

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9
Q

Perlecan

A

PG important for glomerular filtration

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10
Q

Decorin

A

PG used for controlling the size of collagen fibrils

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11
Q

Aggrecan

A

PG found in cartilage

Mechanical support, forms large aggregates with hyaluronic acid…

Binds TGF-beta

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12
Q

A multi-adhesive protein?

A

Usually large secreted protein that has binding sites for both ECM components and a receptor on the cell surface

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13
Q

Fibronectin…location? And to what matrix molecule does it bind?

A

Found in loose connective tissue and provisional wound matrices

Binds to type I collagen fibrin, heparan sulfacte proteoglycan, and membrane intercolated integrins

An isoform of FN also circulates in the plasma

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14
Q

Laminin-1

Location and what does it bind to?

A

Multi-adhesive matrix protein found in the basement membrane

Binding sites for type IV collagen, sulfated lipids, and carbohydrates (primarily heparan sulfate) and integrins

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15
Q

Protein important for neuronal development?

A

Laminin

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16
Q

Protein important in muscular distrophy?

A

Laminin

17
Q

Protein important in wound healing

A

Fibronectin

18
Q

Which cell adhesion molecules mediate interactions between the same cell types?

A

Cadherin and CAMs

19
Q

What types of cell adhesion proteins are utilized in the process of leukocyte extravasation

A

Selectins and integrins

20
Q

Why would an agonist that increases cell adhesion prevent leukocyte extravasaction and subsequent inflammation?

A

The cells bind to tightly that they cannot release to crawl between the endothelial cells

21
Q

Structure of activated vs inactivated integrin?

A

Inactive = folded up…therefore cannot bind to ECM molecules nor transduce signals

Active = ‘unfurls’ to expose a ligand binding site…cytoplasmic domains also disengage from each other and can now transduce signals

22
Q

Integrin presence and function?

Based on the fact that a cell tests postive for beta1 and alpha2 integrin chains

A

It MIGHT bind to collagen…since alpha2beta1 integrin has that specifity

HOWEVER…

Since the beta1 chain can also interact with a large number of other alpha subunits…additional experiments would be required to confirm this

23
Q

What intracellular signaling pathway can be activated by integrin ligation?

A

PI3 kinase pathways (many effects in the cell)

Rho/Rac/cdc42 pathways (primarily cytoskeletal reorganization)

ERK/MAPK pathways (primarily cell proliferation)

24
Q

Clostridium bacteria (gas gangrene)

A

Express type IV collagenases to allow invasion deeper into tissues

Cancers can do the same thing

25
Q

Function of the hydrated gel

A

Absorb and retain water for lubrication

26
Q

Charge of GAGs and what that allows them to do

A

They are negatively charged and highly polar

Allows them to attract/absorb water —> useful to the body as a lubricant and shock absorber

27
Q

Duchenne vs. Becker muscular dystrophy?

A

Duchenne = absence of expression of dystrophin protein in cytosol

Becker = lower expression/less functional dystrophin protein

28
Q

Dystrophin protein

A

Holds cytoskeleton plasma membraneECM

Important with muscle cells b/c they expand and contract so much

29
Q

Alpha-beta-dystroglycan

A

Member of the sarcoglycan membrane complex…which helps connect the internal cytoskeleton to the ECM

Specifically…connect laminin matrix proteins in the basal lamina of muscles

30
Q

Cadherin

What it binds to =

Location =

Function =

A
  1. Cadherin
  2. Desmosomes
  3. Mediate adhesion between cells during development (allowing tissue formation)
31
Q

NCAM

What it binds to?

Location?

Function?

A
  1. NCAM
  2. Neurons and muscle
  3. Neuronal development and have a similar structure to immunoglobulin molecules
32
Q

Integrin

What it binds to to

Location

Function

A
  1. Fibronectin
  2. Multiple cell types
  3. Allows communication across the plasma membrane…interacts with cytoskeleton
33
Q

Selectin

What it binds to

Location

Function

A
  1. Glycoprotein
  2. WBCs and endothelial cells
  3. Movement of WBCs (extravasation)
34
Q

Resting state in the extravasation process…

A

Resting state=

selectin ligand is actively expressed

Alpha-L-beta-2 integrin is inactive

P-selectin molecule is within vesicles in the endothelial celsl

35
Q

After injury is detected in tissue (extravasation) —>

A
  1. Platelet activating factor (PAF) released —> P-selectin released
  2. When P-selectin is loosely attached to the selectin ligands —> leukocyte starts to ‘roll’ towards the affected tissue
  3. Leukocyte is now activated and the released PAF goes on to activate alpha-L-beta-2 integrin molecule on the leukocyte
  4. Alpha-L-beta-2 integrin molecules bind with ICAM molecules on endothelial surface…and PAF (on endothelial surfaces) binds to PAF receptor (on leukocyte)
  5. Integrin/ICAM interaction allows the WBC to migrate through the endothelium into the underlying tissue to increase inflammation
36
Q

Multiple sclerosis

A

When the immune system attacks myelin within the CNS and causes hyper-inflammation within the body

37
Q

Natalizumab

A

Antagonistic drug therapy for MS

Binds to alpha-L-beta2 integrin subunit

Allows WBC to keep rolling through blood vessel without resulting in immune system destruction

38
Q

MS agonist drug therapy

A

ALB2 integrin agonist binds to WBC so tightly to the integrin molecule that it cannot move into the cell

Biggest reduction of inflammation but can cause immune system destruction

39
Q

Role of integrin

A

Play huge role in cell cycle regulation…

Obligate heterodimer (type of CAM)

Binds to fibronectin

Biochemistry Muscoskeletal (8 decks)

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