Extracellular matrix, cell-cell and cell-substrate adhesion

Question 1

ECM fx.

Answer 1

Scaffold for cells and regulates survival, differentiation, migration, proliferation, and shape.
Amt varies in tissues (less in brain, more in connective tissue)

Question 2

What makes ECM in connective tissues?

Answer 2

Secreted by fibroblasts (chondroblasts specificallly)

Question 3

4 major classes of ECM mlcs?

Answer 3

1. ) Glycosaminoglycans (GAGs), link covalently to proteins to form proteoglycans
2. ) Fibrous proteins: collagen and elastin
3. ) Multidomain adapter proteins: fibronectin, laminin
4. ) Water and many solutes

Question 4

Proteoglycans

Answer 4

Form a gel where fibrous/multidomain mlcs insert. Things can diffuse through (like nutrients).
Can have many gag chains. HEAVY. Core protein has attached to serines special link tetrasaccharides, primers for polysaccharide assembly.
Post-trans modifications take place in golgi.
Has roles in kidney and as reservoirs of GF/proteases.
Can be membrane-bound or higher order aggregates.

Question 5

Basal lamina characteristics?

Answer 5

Collagen IV and laminin Epithelia.

Question 6

GAGs

Answer 6

Made of unbranched polysaccharide chains which are made of disaccharide repeats (one sugar is amino sugar, like N-acetyl-glucosamine) and one is uronic acid.
Sulfation/carboxyl groups give GAGs a neg charge so they can be hydrated!

Question 7

GAG examples

Answer 7

Hyaluronan, chondroitin, dermatan, heparan, keratan (differ in disaccharide composition/sulfate group location)

Question 8

Collagen

Answer 8

Very abundant. Collagen I common, in connective tissues. Collagen IV in basal lamina.

Question 9

Elastin

Answer 9

Important in skin, lungs.

Question 10

Multidomain adpapter proteins

Answer 10

Act as binding sites for other matrix macromlcs and adhesion mlcs on surfaces of cells. HELP ORGANIZE matrix.
Fibronectin, laminin, tenascin.

Question 11

Fibronectin

Answer 11

Large, dimeric glycoprotein. 2 subunits linked by disulfide bond. Each subunit folded into distinct binding domains (made of serially repeated smaller modules)
Main module: type III fibronectin repeat which is important because….
Other domains bind collagen etc.
Secreted fibronectin assembles in ECM into highly insoluble fibronectin fibrils.

Question 12

Fibronectin III repeat

Answer 12

Binds laminin. Module of fibronectin. Contains RGD binding sequence (arg-gly-asp).

Question 13

Laminin

Answer 13

Large. 3 subunits that form asymmetric, disulfide linked cross (long arm by helical structure).
FOUND ONLY IN BASAL LAMINA.
Can self-assemble into network through their arm interactions.
have numerous binding sites for cells/ other things that link them to collagen.

Question 14

MMP

Answer 14

They turn over the ECM. Tissue remodeling, development, invasion etc, reveal sites for more binding/release signals (highly regulated).

Question 15

Adhesion mlcs.

Answer 15

CAMs.
Not just adhesion devices.
Can form TM link with cytoskeleton for force. When bound to ligand their have conformational change in cell interior, affect cell fx.

Question 16

3 classes of CAMs

Answer 16

Cadherins
Ig Superfamily (IgSF) CAMs
Integrins

Question 17

Cadherins

Answer 17

SINGLE PASS TM glycoproteins. Operate as homodimers.
Extracellular domain has 5 repeats stabilized by Ca to make a ROD. (so binding is Ca dependent)
Bind to other cell with cadherins, zipper.

Question 18

IgSF CAMs

Answer 18

SINGLE PASS Tm glycoproteins.
HOMOPHILIC binding mechanism.
Do NOT form dimers, binding does NOT require Ca (mediated by Ig domains).

Question 19

Integrins

Answer 19

Binding is Heterophilic.
Composed of alpha beta heterodimers. Many diff alpha beta subunits exist so get lots of avariety!
typical ligands: fibronectin, laminin etc. (often involved RGD sequence).

Question 20

How do CAM’s link to cytoskeleton?

Answer 20

Proteins associated with cytoplasmic tails of CAMs, they contain actin binding proteins,
Catenins are assoicated proteins.

Question 21

What do CAM associated proteins do?

Answer 21

Cytoskeletal link, adhesion regulation, control of actin polymerization, cell signaling.

Question 22

Examples of ECM disease

Answer 22

Collagen mutations (osteogenesis)
Overexpression of MMPs (poor prognosis in cancer)

Question 23

Cell adhesion and disease

Answer 23

CAM loss of fx can be lethal to embryo.
Cancer early sign is CAm change.
Certain catenins are tumor suppressors.