MULTICELLULAR ORGANISMS

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MULTICELLULAR ORGANISMS

• Cell-Cell Adhesion
• Cell-Matrix Adhesion
• The Extracellular Matrix, ECM

Http//www.plab.ku.dk/bock/index.htm Link
Multicellular organisms
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MULTICELLULAR ORGANISMS

• The appearance of multicellular organisms allows
  specialization of cells and formation of organs
• Vertebrates have more than 100 specialized cell
  types (plants have more than 15)
• A special matrix, the extracellular matrix, ECM,
  fills out the space between cells
• ECM also binds cells together, acts as reservoir
  for growth factors and hormones, and creates an
  environment in which molecules and cells can
  migrate

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MULTICELLULAR ORGANISMS

• By means of cell adhesion molecules, CAMs, cells
  are capable of recognizing each other
• Plasma membrane receptors take care of cell-ECM
  interactions
• Fig. 22-1

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CELL JUNCTIONS

• Adherens junctions
• Gap junctions
• Tight junctions
• Desmosomes/Hemidesmosomes
• Focal adhesions

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CELL-CELL ADHESION MOLECULES

• Cadherins
• Ig superfamily CAMs
• Selectins
• Integrins
• Connexins
• Occludin and claudin proteins
• Fig. 22-2

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CADHERINS

• A family of Ca2-dependent CAMs
• Ca2 causes dimerization of Cadherins
• The binding is homophilic
• Table 22-1
• Fig. 22-5
• Fig. 22-6

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SELECTINS

• Selectins are involved in extravasation
• Inflammatory signals activate endothelial cells
  making P-Selectin undergo exocytosis
• P-Selectin on the surface of endothelial cells
  binds a specific carbohydrate ligand (Sialyl
  Lewis -x) on leukocytes
• The leukocytes attach to the endothelial wall and
  roll slowly on it
• PAF and integrins are then activated and the
  leukocytes start to extravasate
• Fig. 22-4

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GAP JUNCTIONS 1

• A cluster of channels between two plasma
  membranes
• Each membrane contain a hemichannel called a
  connexon made of 6 subunits - connexins
• There are 12 different connexin genes
• Usually connexons are hetero-oligomeric and the
  composition determines permeability
• Fig. 22-7
• Fig. 22-8

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GAP JUNCTIONS 2

• Allow particles of
• Ions, ATP, cAMP can pass I.e. hormonal
  stimulation of one cell can spread to connected
  cells, and thereby organize coordinated functions
  such as secretion, contraction, movement of cilia
• The channels close at increased Ca2
  concentrations allowing regulation of the degree
  of coupling to surrounding cells

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CELL-MATRIX ADHESION

• Integrins
• Collagens
• Laminin and Fibronectin
• Proteoglycans and Glucosaminoglycans

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CELL MATRIX ADHESION

• Integrins on the cell surface mediate cell-ECM
  binding
• Integrins are composed of an??- and a ?-chain
• There are 3 different ?-chains and more than 10
  types of ?-chains
• The chain composition determines the ligand
  specificity
• The affinity is generally low (Kd 10-6 -10-8)
• Table 22-2

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INTEGRINS

• Integrins can be activated through a signal from
  the interior of the cell
• Activation involves conformational changes of
  the integrin
• Various integrins recognize specific sequences in
  their ligands. E.g. ?4?1 recognizes EILDV (in
  VCAM-1 and in fibronectin) and ?5?1 recognizes
  RGD in many ECM proteins

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INTEGRIN CONTAINING JUNCTIONS

• A junction consists of an exterior ligand, a
  transmem-brane protein, a linker, and a
  cytoskeletal component
• An adherence junction connects an ECM component
  with an integrin linked to an adapter (e.g.
  vinculin) and F-actin
• A hemidesmosome connects an ECM-component to
  integrin and via an adapter (e.g. plectin) to
  intermediate filaments (keratins)
• Fig. 22-10a

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DISINTEGRINS

• Disintegrins contain the RGD sequence and
  interfere with integrin-ECM adhesion allowing
  deadhesion and cell migration
• The ADAMs (A Disintegrin And a Metalloprotease)
  remodel surface proteins f.x. at the fusion of
  sperm and egg, the fusion of myoblasts during
  myogenesis, release of TNF? from the surface

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COLLAGENS

• The most abundant animal protein
• At least 16 types exist
• The structural unit is composed of three 300 nm
  long coiled subunits in a triple helix
• The helical structure depends on the abundant
  presence of glycin, proline (and hydroxyproline)
  making a motif gly-pro-x, which is necessary for
  twisting together the three strands
• Table 22-3
• Fig. 22-11

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COLLAGENS 2

• Collagens are synthesized as precursors called
  procollagens
• They are glycosylated in ER and Golgi adding Gal
  and Gly to hydroxy-lysine residues and long
  oligosaccharides to selected asparagine residues
• Proline and lysine are hydroxylated
• Disulphide bonds are made between the N- and
  C-terminal parts of the propeptides
• After exocytosis the N- and C-terminals are
  trimmed, only then can the fibrils be formed
• Fig. 22-14

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COLLAGENS 3

• Lack of vitamin C prevents hydroxylation ?
  impaired fibrils
• Mutations or deletions of ?-chains in Collagen I
  can lead to the disease Osteogenesis imperfecta
• Fig. 22-15

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COLLAGENS 4

• Collagens can form various types of fibres and
  networks
• Fig. 22-16
• Fig. 22-17

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LAMININ

• Laminin is a key component of the basal lamina
• Fig. 22-18
• Fig. 22-21
• Fig. 22-19
• Fig. 22-20

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FIBRONECTIN

• Fibronectins attach cells to collagens
• Fibronectins are dimers
• Fibronectins express the RGD sequence recognized
  by integrins
• Fig. 22-22
• Fig. 22-23

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PROTEOGLYCANS 1

• The Polysaccharides in proteoglycans are long
  repeating polymers of dissacharides called
  Glucosaminoglycans (GAGs)
• One sugar of the dissacharides is a uronic acid
  and the other is an aminosugar (e.g.
  N-acetylglucosamine)
• One or both sugars contain one or two sulphate
  residues
• Fig. 22-24

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PROTEOGLYCANS 2

• Heparin sulphate and chondroitin sulphate are
  added to a 3-sugar linker (Xyl-Gal-Gal) added
  to a Serine in the core protein
• Proteoglycans are found both in ECM and attached
  to the plasma membrane
• Fig. 22-25

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PROTEOGLYCANS IN THE ECM

• In cartilage the key proteoglycan is aggrecan
• The central component of aggrecan is a
  carbohydrate, hyaluronan
• At 40 nm intervals aggrecan core proteins are
  attached (assisted by a linker protein) to a
  decasaccharide sequence in hyaluronan
• Attached to the aggrecan core protein are
  multiple GAGs (via the trisaccharide linker)
• The GAGs in aggrecan are chondroitinsulphate and
  keratin sulphate
• MW of an aggrecan 2 x 108
• Fig. 22-26

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PROTEOGLYCANS ON THE CELL SURFACE

• A typical example is syndecan
• The core protein spans the membrane with a short
  cytosolic domain
• The GAGs are attached via the trisaccharide
  linker to serine residues
• The GAGs in syndecan are heparan sulphate chains
• Syndecan binds extracellularly to collagens and
  fibronectin and intracellularly to the
  cytoskeleton
• Fig. 22-27
• Fig. 22-28

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HYALURONAN (HA)

• HA is a GAG found in ECM
• HA is also a key component of complex
  proteoglycans
• HA consists of approx. 50,000 disaccharides in a
  random coil. It can be bound to the surface
  receptor CD44
• HA gives strength, flexibility and smoothness to
  the ECM and forms a viscous hydrated gel in which
  cells can migrate
• HA makes the ECM able to resist compression