2009 Lecture 13

From CellBiology

Extracellular Matrix 1

Cell Adhesion
Collagen (type I) Fibres
Collagen triple helix


This lecture introduces the materials lying outside the cell, known collectively as the extracellular matrix (ECM). There is no one matrix though, with different tissues having their own specific ECM, which may be dynamic or static in structure. In particular the ECM has significant roles in normal tissue development, function and disease. This matrix is manufactured by cells, secreted and modified outside the cell by several different enzymes.

This first lecture introduces the ECM and describes the major fiber (fibre) and matrix components, the second lecture will cover the major ECM glycoproteins and experimental studies of ECM function.

Spelling - UK sulphate, US sulfate ; UK fibre, US fiber

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(MH - note that content will not match exactly current lecture structure but has been selected as having similar content)

ECM Function

  • Support for cells
  • Pattern of ECM regulates
    • polarity
    • cell division
    • adhesion
    • motility
  • Development
    • migration
    • differentiation
    • growth factors

ECM Features

  • stable and able to be reorganised?
  • different for different tissues

19-61. How the extracellular matrix could, in principle, propagate order from cell to cell within a tissue

ECM Structure

  • Glycoproteins
  • Fibers
    • Collagen- main fibers
    • Elastin
  • Hydrated Matrix
    • Proteoglycans
    • high carbohydrate
  • Adhesive
    • Laminin
    • Fibronectin

Shapes and Sizes ECM molecules

  • Note the relative size and differential contribution of protein (green) and glycosaminoglycan (red)


  • tensile strength and elasticity
    • Tendons
    • Cartilage
    • Bone
  • half total body proteins (by weight)

Collagen Components

  • Insoluble glycoprotein
    • protein + carbohydrate


  • high glycine and 2 modified amino acids
  • hydroxylysine
  • hydroxyproline
  • (gly-X-Y)n


  • glucose
  • galactose

Collagen Structure

Collagen Fiber structure and size

Collagen Protein

  • 3 polypeptide (a) chains
  • left hand helix, forms fibers
  • many different (vertebrate) collagens by different combinations of a-chains
  • Type I, II, III
    • main fibers, flexible
  • Type I
    • bone, skin, tendons
    • 90% of all collagen
  • Type II
  • cartilage

Collagen Fibers

Collagen Type I
  • Type I, II, III cross striated
    • e.g. tendons - type I fibrils, have a 67-nm period striations and are oriented longitudinally (direction of the stress)
    • showing overlapping packing of individual collagen molecules
    • reticular fibres type III, support individual cells
  • Type IV fine unstriated
    • sheet-like supportive meshwork
    • mature basal laminae
    • tracks for embryonic migration
    • barriers for cell migration
  • Type V-XII
    • smaller diameter fibers than I-III
    • no striations

Collagen Fibers Collagen Non-striated

Collage Interactions

Collagen fibril types can interact with a variety of non-fibrous collagen types (microfiber)

  • fibrous collagens—types I, II, III, and V
    • Cartilage - types II (fiber) and IX collagen microfibrils
    • Tendons - type I fibrils bound and linked by type VI microfibrils.

Interactions of fibrous and nonfibrous collagens

Collagen Type Functions

  • Collagen Type I - skin, tendon, vascular, ligature, organs, bone (main component of bone)
  • Collagen Type II - cartilage (main component of cartilage)
  • Collagen Type III - reticular fibers with type I.
  • Collagen Type IV - forms bases of cell basement membrane

MH - You do not need to know the protein table below in detail, just the major type/functions show above.

Collagen Proteins

Collagen type
Organization in tissues (where known) References
Fibrils in tendon, bone, skin, cornea and blood vessel walls Chu et al., 1982
Myers et al., 1981
Fibrils in cartilage Miller and Matukas, 1969
Forms heterotypic fibrils with type I collagen Cameron et al., 2002
Network in basement membrane Timpl and Brown, 1996; Timpl et al., 1981
Forms heterotypic fibrils with type I Birk, 2001
Fine microfibrils with ubiquitous distribution (distinct from fibrillin- Kielty et al., 1992
containing microfibrils
Forms anchoring fibrils in skin at the dermal/epidermal junction Keene et al., 1987
(basement membrane)
3D hexagonal lattice in Descemet's membrane in the eye Kapoor et al., 1986; Kapoor et al., 1988;
Stephan et al., 2004
Associated with type II collagen fibrils Olsen, 1997; Shimokomaki et al., 1990
Mat-like structure/hexagonal lattice in the hypertrophic zone of the growth plate Kwan et al., 1991
Forms heterotypic fibrils with type II Mendler et al., 1989
Associated with type I fibrils Keene et al., 1991; Nishiyama et al., 1994;
Zhang et al., 2003
Transmembrane and possibly involved in cell adhesion Latvanlehto et al., 2003
Associated with type I fibrils Young et al., 2000b; Young et al., 2002
Specialized basement membranes, cleaved to produce antiangiogenic Myers et al., 1996; Ramchandran et al.,
fragment (restin) 1999
Component of specialized fibrillin-rich microfibrils in skin and type II Kassner et al., 2003
collagen fibrils in cartilage
Transmembrane component of hemidesmosomes (cell-cell junctions), which Hopkinson et al., 1998
attach epidermis to basement membrane in skin
Cleaved to produce antiangiogenic fragment (endostatin) Sasaki et al., 1998
Radially distributed aggregates formed by association at one end in vitro Myers et al., 2003
May be associated with type I collagen fibrils Koch et al., 2001
May be fibril associated, widespread expression pattern Fitzgerald and Bateman, 2001
Located in specific tissue junctions and may be associated with microfbrils Koch et al., 2004
Transmembrane collagen identified in cell culture Banyard et al., 2003
Expressed in tissues containing type I collagen Koch et al., 2003
Transmembrane collagen, cleaved form present in Alzheimer‚ amyloid plaques in neurons Hashimoto et al., 2002
  • Table modified from Canty EG, Kadler KE. Procollagen trafficking, processing and fibrillogenesis. J Cell Sci. 2005 Apr 1;118(Pt 7):1341-53. Review. PMID: 15788652 | JCS Link

Collagen Synthesis

* Endoplasmic Reticulum
    • mRNA attached to ER
    • protein synthesized into ER lumen
    • cotranslational and post-translational modifications
    • 3 proto-a-chains form soluble procollagen
    • moved to golgi apparatus
  • Golgi Apparatus
    • packed into secretion vesicles
    • fuse with membrane
Collagen synthesis
  • Outside Cell
    • procollagen processed by enzymes outside cell
    • assemble into collagen fibers
    • collagen fibrils form lateral Interactions of triple helices

Collagen fibril assembly

Collagen Biosynthesis

Collagen Diseases

Collagen Diseases - Excess

  • fibrosis
  • lung- pulmonary fibrosis
  • overproduction of collagen I
  • liver- over consumption of alcohol
  • arteries- atherosclerosis

Collagen Diseases - Insufficient

  • Ehlers-Danlos syndrome
    • rubber-man
    • skin and tendons easily stretched
    • contortionists often suffer from this disease
  • Osteogenesis imperfecta
    • brittle-bone syndrome
    • mutation in Type I procollagen
    • fail to assemble triple helix
    • degrade imperfect collagen
    • Leads to fragile bones
  • Scurvy
    • dietary Vitamin C deficiency
    • needed for hydroxylation
    • Proline -> Hydroxyproline
    • form too few hydrogen bonds in collagen
    • skin, bone, teeth weakness and malformation
    • blood vessels weakened, bleeding
  • Atopic dermatitis (AD)
    • chronic inflammatory skin disorder and a major manifestation of allergic disease
    • mutation in collagen XXIX (COL29A1) gene


Elastic Fibers Skin
  • elastin and elastic fibres
    • uncoils into an extended conformation when the fiber is stretched
    • recoils spontaneously as soon as the stretching force is relaxed

Elastic fibers are composed of a core of cross-linked elastin embedded within a peripheral mantle of microfibrils.


  • may regulate assembly and organization of elastic fibers by acting as a scaffold
  • guiding tropoelastin deposition
  • aggregates of threadlike filaments
  • periodically spaced globular domains (beads) connected by multiple linear arms
    • beaded structure is parallel fibrillin monomers aligned head-to-tail
  • fibulin-5 induces elastic fiber assembly and maturation by organizing tropoelastin and cross-linking enzymes onto microfibrils PMID: 17371835

Elastin Structure

  • protein Mr 64 to 66 kDa
  • composed of the amino acids glycine, valine, alanine, and proline
  • cross-linked tropoelastin monomers
  • first secreted as soluble precursors (tropoelastin)
  • assembly and crosslinking of tropoelastin monomers
  • form insoluble elastin matrix into functional fibres
    • lysine residues in the cross-linking domain of secreted tropoelastin rapidly cross-linked (both inter- and intra-molecularly by lysyl oxidase)
    • hydrophobic segments - elastic properties
    • α-helical segments (alanine- and lysine-rich) - form cross-links between adjacent molecules

Elastin Function

  • structural integrity and function of tissues
  • requiring reversible extensibility or deformability
  • high levels in tissues that require elasticity
    • lung, skin, major blood vessels

Elastin Disorders


  • consist of protein (~5%) and polysaccharide chain (~95%)
  • form a gel to embed the fibril network
  • Golgi apparatus - GAG disaccharides are added to protein cores to form proteoglycans
  • 10% by weight but fill most of space
  • unbranched polysaccharide chains
  • disaccharide subunits
  • amino sugar

Glycosaminoglycans (Gags)

Five types

  • Hyaluronan (or hyaluronic acid) main glycosaminoglycan in connective tissue
  • high molecular weight (~ MW 1,000,000 )
  • length of about 2.5 µm hyaluronan i
  • "backbone" for the assembly of other glycosaminoglycans
    • Hyaluronan is also a major component of the synovial fluid, which fills joint cavities, and the vitreous body of the eye.
  • Other 4 major glycosaminoglycans
    • chondroitin sulphate, dermatan sulphate, keratan sulphate and heparan sulphate (UK sulphate, US sulfate)
    • attach through core and link proteins to hyaluronic acid backbone

Proteoglycan Function

  • trap water
  • resistant to compression
  • return to original shape
  • occupy space
  • link to collagen fibers
  • form network
    • in bone combined with calcium hydroxyapatite, calcium carbonate


  • produce a “cell-free” space
  • for cell proliferation and migration into
  • heart, cornea


  • in areas of compression
  • tissues, joints

hyaluronan-binding proteins

Hyaluronan Synthesis

  • differs from other GAG synthesis
    • synthesized at plasma membranes
    • nascent chains directly extruded into ECM

Cell adhesion

embryonic migration

Proteoglycan- Disease

  • Mucopolysaccharidosis type I (MPS I) - Hurler disease
  • lysosomal storage disease, is associated with an altered elastic matrix
  • excess heparan sulphate and dermatan sulphate
  • Cancer development
    • altered types and kinds of proteoglycans formed by cells
    • normal cells -> malignant
  • Arthritis
    • Cartilage breakdown (cartilage erosion)
    • chondrocytes elicit a catabolic response which exceeds anabolism of new matrix molecules
    • Degrade proteoglycan (aggrecan)
    • Also a mouse model generates antibodies to proteogycan


Below are some example historical research finding related to cell junctions from the JCB Archive.

1978 Basal lamina instructs innervation Joshua Sanes and Jack McMahan show that regenerating nerve axons take their cues for new synapse formation from the extracellular matrix (ECM) of muscle cells and not from the muscle cells themselves.



Essential Cell Biology

  • Essential Cell Biology Chapter 19 p594-604

Molecular Biology of the Cell

Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002

  • Molecular Biology of the Cell 4th ed. - V. Cells in Their Social Context Chapter 19. Cell Junctions, Cell Adhesion, and the Extracellular Matrix
  • The Extracellular Matrix of Animals

Molecular Cell Biology

Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999

The Cell- A Molecular Approach

Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

  • The Cell- A Molecular Approach
  • The Cell - A Molecular Approach - III. Cell Structure and Function Chapter 12. The Cell Surface
  • The Extracellular Matrix

Essentials of Glycobiology, 2nd ed.

Varki, A.; Cummings, R.D.; Esko, J.D.; Freeze, H.H.; Stanley, P.; Bertozzi, C.R.; Hart, G.W.; Etzler, M.E., editors Plainview (NY): Cold Spring Harbor Laboratory Press; 2008

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Canty EG, Kadler KE. Procollagen trafficking, processing and fibrillogenesis. J Cell Sci. 2005 Apr 1;118(Pt 7):1341-53. Review. PMID: 15788652 JCS Link

  • Hay ED. The extracellular matrix in development and regeneration. An interview with Elizabeth D. Hay. Int J Dev Biol. 2004;48(8-9):687-94. No abstract available. PMID: 15558460
  • Hay ED. Extracellular matrix. J Cell Biol. 1981 Dec;91(3 Pt 2):205s-223s. Review. No abstract available. PMID: 6172429
  • Sandberg LB, Soskel NT, Leslie JG. Elastin structure, biosynthesis, and relation to disease states. N Engl J Med. 1981 Mar 5;304(10):566-79. Review. PMID: 7005671
  • Wagenseil JE, Mecham RP. New insights into elastic fiber assembly. Birth Defects Res C Embryo Today. 2007 Dec;81(4):229-40. Review. PMID: 18228265


  • Sandberg LB, Soskel NT, Leslie JG. Elastin structure, biosynthesis, and relation to disease states. N Engl J Med. 1981 Mar 5;304(10):566-79. Review.

PMID: 7005671


  • Synthesis animated cartoon
  • Marfan syndrome is an autosomal dominant disorder that has been linked to the FBN1 gene on chromosome 15. FBN1 encodes a protein called fibrillin

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