What are proteoglycans?

GLYCOCONJUGATES =

 Essentially PROTEIN and GLYCANS. 

 

Consist of a protein core which has one or more covalently attached glycosaminoglycan (GAG) chain(s).

 

Made by virtually all animal cells.

 

Huge functional diversity.

 

NB - Hyaluronan is not found covalently attached to proteoglycans but can non-covalently interact with proteoglycans.



Proteoglycan structure

PROTEOGLYCAN STRUCTURE = HIGH VARIABILITY

 

Core protein

  • Synthesised in the rough endoplasmic reticulum (RER).

 

  • 10kDa - >500kDa.

 

GAG chains

  • Synthesised in the endoplasmic reticulum (ER)-Golgi pathway (GAGosomes).

 

  • Highly variable

 

  • Varying numbers added to protein cores.

 

  • Physiological function of proteoglycans are mostly mediated by GAG chains.


Where are they found and what do they do?



INTRACELLULAR PROTEOGLYCANS

 

    • Found mostly in secretory granules.

     

    • Control the storage of enzymes and compounds inside the secretory granules.

     

    • The high negative charge of GAGs can control the availability of positively charged components in secretory granules by sequestering them (e.g proteases).

         

        EXAMPLES

         

        Serglycin

        • Main secretory granule proteoglycan.
        • Can carry CS or heparin chains (only in connective tissue mast cells).

        NB - heparin is a GAG which is a more highly sulphated analogue of HS found only in mast cells.

        Chromogranin A

         

        CELL MEMBRANE PROTEOGLYCANS

         

        Membrane spanning - Syndecans.

         

        GPI anchored - Glypicans.

         

        Often extend from the cell surface into the ECM.

         

        Functions mostly include cell signalling - modifying intracellular signalling pathways in response to extracellular ligands.

         

        Other examples of cell membrane proteoglycans include neuropilin-1, NG2, betaglycan and CD44

        Syndecans

        Extracellular domain 

        Larger domain, site of GAG attachment and interacts with extracellular ligands.

        Can be cleaved and shed into the extracellular matrix (ectodomains).

         

        Short hydrophobic domain

        Spans the plasma membrane.

         

        Intracellular domain

        Smaller than extracellular domain.

        Attaches to the actin cytoskeleton and recruits intracellular signalling proteins in response to receptor oligomerisation / clustering.

         



        Glypicans

         

        GPI-anchored membrane protein.

         

        Extracellular globular domain.

        Can be shed into the extracellular environment. Largely through action of the extracellular lipase notum which cleaves the GPI anchor.

         

        Heparan sulphate proteoglycans

        Glypicans exclusively carry HS GAG chains.

         

        • 6 isoforms in humans and mice.
        • Main functions are to regulate growth factor signalling -Wnt, Hhs (Hedgehogs), FGF (Fibroblast growth factor), BMP (bone morphogenic protein).
        • Other functions have been reported including synapse morphogenesis and polyamine uptake.

        EXTRACELLULAR PROTEOGLYCANS

         

        Secreted into the extracellular matrix.

         

        Key components of the extracellular matrix - many diverse structures and functions!

        • Provide a hydrated gel which allows the extracellular matrix to resist compressive forces.
        • Growth factor regulation.

         

        Large variety of molecules which can be loosely grouped into families. There are lots so pick your favourites....

         



        Aggrecan family



        Small leucine rich proteoglycans (SLRPs)



        Perlecan

        Basement membrane proteoglycan, but also found in the interstitial matrix of some tissues.

        Key component of vascular ECM.

        Large multidomain core protein.

        Predominantly has HS chains attached but CS chains can also be attached.

        Can bind and crosslink many ECM and cell surface molecules. These interactions can be dependent upon or influenced by attached GAG chains, or the perlecan core protein can interact independently.

        Theory that perlecan functions as an ECM scaffold linking the ECM to the cell surface.

        Perlecan has functions in angiogenesis, chondrogenesis and endochondrial ossification.

        Agrin

        Basal lamina proteoglycan.

        Has HS chains attached.

        Important in the development of the neuromuscular junction during embryogenesis.

        Collagen type XVIII

        Found in the basement membrane.

        Carries HS chains, and is the only known collagen to carry HS chains.

        HS chains aid binding of collagen XVIII to the basement membrane.

        Has structural properties of both a collagen and a proteoglycan.

        Important for blood vessel development in the eye.

        C-terminal proteolytic cleavage yields endostatin which has been shown to be anti-angiogenic.

         

        References

        http://www.ncbi.nlm.nih.gov/books/NBK1900/ - whole text of essentials of glycobiology is available online!

        http://genomebiology.com/2008/9/5/224

        http://www.uscnk.com/directory/Serglycin(SRGN)-2869.htm

        http://www.biology-online.org/articles/structure_function_cartilage_proteoglycans/slrps.html

        (all websites accessed prior to 29/06/2012)

         

        Couchman, J.R (2010) Transmembrane signalling proteoglycans. Annual review of cell and developmental biology. 26: 89-114

        Dong, S (2002) Expression of collagen XVIII and localisatino of its GAG attachment sites. The journal of biological chemistry. 278: 1700-1707

        Farach-Carson, MC (2007) Perlecan - a multifunctional extracellular proteoglycan scaffold. Glycobiology. 17(9):897-905

        Fukai, N (2002) Lack of collagen XVIII/endostatin results in eye abnormalities. The EMBO journal. 21: (1535-1544)

        Kiari, C (2002) Structure and function of aggrecan. Cell Res. 12(1): 19-32

        Knox, S.M (2006) Perlecan: how does one molecule do so many things? Cellular and molecular sciences. 63(2):2435-2445

        Perrimon, N (2001) Cellular functions of proteoglycans - an overview. Seminars in cell and developmental biology. 12: 65-67

        Wight, TN (2002) Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr opin cell biol. 14(5):617-623

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