Proteoglycans

Proteoglycans are proteins that are heavily glycosylated*. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s).

1. Proteoglycans Proteoglycans  are proteins that are heavily glycosylated *. The basic  proteoglycan  unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). * Glycosylation   is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) .

2. A  glycosyl  group is a univalent free radical or substituent structure obtained by removing the hemiacetal hydroxyl group from the cyclic form of a monosaccharide and, by extension, of a lower oligosaccharide. Glycosyl - a radical derived from a carbohydrate.  glycosyl   transferases . enzymes catalyzing the transfer of a monosaccharide  unit  from a nucleotide-linked sugar to the non-reducing end of an oligosaccharide chain, or to an appropriate functional group on a protein.

3. (Schematic structure of glycosaminoglycan and proteoglycan . Note that the hyaluronic acid is not linked to a protein core. Heparan sulphate , dermatan sulphate and chondroitin sulphate are connected to proteoglycan via a serine residue). Serine  proteases (or  serine   endopeptidases ) are enzymes that cleave peptide bonds in proteins , in which  serine  serves as the  nucleophilic   amino acid  at the (enzyme's)  active site .  They are found ubiquitously in both  eukaryotes  and  prokaryotes .  This specificity is driven by the  residue  which lies at the base of the enzyme's S1 pocket (generally a negatively charged aspartic acid or glutamic acid). glucuronic acid ( GlcA ) N- Acetylgalactosamine ( GalNAc ), is an amino sugar derivative of galactose .

4. Hyaluronic acid  (D- glucuronate + GlcNAc ) Occurence  : synovial fluid, ECM of loose connective tissue Hyaluronic acid  is unique among the GAGs because it does not contain any sulfate and is not found covalently attached to proteins. It  forms non-covalently linked complexes   with proteoglycans in the ECM. Hyaluronic acid polymers are very large (100 - 10,000 kD ) and can displace a large volume of water. Dermatan sulfate  (L-iduronate + GlcNAc sulfate ). Occurence  : skin, blood vessels, heart valves Chondroitin sulfate  (D-glucuronate + GalNAc sulfate ). Occurence  : cartilage, bone, heart valves ; It is the most abundant GAG . Heparin and heparan sulfate  (D- glucuronate sulfate + N- sulfo -D-glucosamine ). Heparans have less sulfate groups than heparins  . Occurence  :  Heparin   : component of intracellular granules of mast cells lining the arteries of the lungs, liver and skin . Heparan sulfate  : basement membranes, component of cell surfaces Keratan sulfate  ( Gal + GlcNAc sulfate ). Occurence  : cornea, bone, cartilage ; Keratan sulfates are often aggregated with chondroitin sulfates.

5. Crystal structure   of   Trypsin , a typical serine protease . A  covalent  bond, also called a molecular bond, is a chemical bond that involves the sharing of electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs, and the stable balance of attractive and repulsive forces between atoms, when they share electrons, is known as  covalent bonding . Serine  proteases (or  serine endopeptidases ) are enzymes that cleave peptide bonds in proteins, in which serine  serves as the nucleophilic amino acid at the (enzyme's) active site. ...  Serine  proteases fall into two broad categories based on their structure: chymotrypsin -like ( trypsin -like) or subtilisin -like. Serine endopeptidases E ndoproteinase are proteolytic peptidases that break peptide bonds of non-terminal amino acids (i.e. within the molecule), in contrast to Exopeptidases , which break peptide bonds from end-pieces of terminal amino acids.

6. Proteoglycans are glycosylated proteins which have covalently attached highly anionic glycosaminoglycans (GAG). Many forms of proteoglycans are present in virtually all extracellular matrices of connective tissues. The major biological function of proteoglycans derives from the physicochemical characteristics of the glycosaminoglycan component of the molecule, which provides hydration and swelling pressure to the tissue enabling it to withstand compressional forces . This function is best illustrated by the most abundant proteoglycan in cartilage tissues, aggrecan . Specific interactions between proteoglycans (through both their glycosaminoglycan and core protein components) and macromolecules in the extracellular matrix are the key factors in the functions of proteoglycans . Exciting biological functions of proteoglycans are now gradually emerging. ( Yanagishita M . Acta Pathol Jpn .  1993 Jun;43(6):283-93. Function of proteoglycans in the extracellular matrix .)

7. Proteoglycans -Functions During the past decade, diverse species of proteoglycans have been identified in many connective tissues, on cell surfaces and in intracellular compartments. These proteoglycans have distinct biological functions apart from their hydrodynamic * functions, and their involvement in many aspects of cell and tissue activities has been demonstrated. For example, decorin , which is widely distributed in many connective tissues, may have functions in regulating collagen fibril formation and in modifying the activity of transforming growth factor-beta; perlecan , the major heparan sulfate proteoglycan in the glomerular basement membrane, may play an important role as the major anionic site responsible for the charge selectivity in glomerular filtration. *hydrodynamics  (the study of liquids in motion)/ hydrodynamic  often means " hydrodynamically efficient".

8. Decorin -binding proteins (DBPs), DBPA and DBPB, are surface lipoproteins on Borrelia burgdorferi , the causative agent of Lyme disease. DBPs bind to the connective tissue proteoglycan decorin and facilitate tissue colonization by the bacterium. Although structural and biochemical properties of DBPA are well understood, little is known about DBPB. In current work, we determined the solution structure of DBPB from strain B31 of B. burgdorferi and characterized its interactions with glycosaminoglycans (GAGs). Our structure shows that DBPB adopts the same topology as DBPA, but possesses a much shorter terminal helix, resulting in a longer unstructured C-terminal tail, which is also rich in basic amino acids. Characterization of DBPB-GAG interactions reveals that, despite similar GAG affinities of DBPA and DBPB, the primary GAG-binding sites in DBPB are different from DBPA. In particular, our results indicate that lysines in the C-terminus of DBPB are vital to DBPB's ability to bind GAGs whereas C-terminal tail for DBPA from strain B31 only plays a minor role in facilitating GAG bindings. Furthermore, the traditional GAG-binding pocket important to DBPA-GAG interactions is only secondary to DBPB's GAG-binding ability. Decorin  is a  protein  that in humans is encoded by the DCN  gene . Decorin is a  proteoglycan  that is on average 90 - 140  kilodaltons  ( kDa ) in molecular weight. It belongs to the small leucine -rich proteoglycan (SLRP) family and consists of a protein core containing  leucine repeats  with a  glycosaminoglycan  (GAG) chain consisting of either  chondroitin sulfate  (CS) or  dermatan sulfate  (DS).

9. Decorin Crystal structure of the dimeric protein core of decorin , the archetypal small leucine -rich repeat proteoglycan

10. Model structure of human decorin with a single triple helix of collagen type I. A is a decorin model in a ribbon representation showing the LRRs* forming a central cavity with the β-sheet on the inner concave surface and the α-helices on the outer convex surface and the a-helices on the ouetr convex Irene T. Weber et al. J. Biol. Chem . 1996;271 : 31767-31770 * Leucine repeat rich proteins

11. Selected items Items: 1 to 20 of 132 Function of proteoglycans in the extracellular matrix . Yanagishita M. Acta Pathol Jpn . 1993 Jun;43(6):283-93. Review. PMID:  8346704 Similar articles Select item 82982462. Proteoglycans and hyaluronan in female reproductive organs . Yanagishita M. EXS. 1994;70:179-90. Review. PMID:  8298246 Similar articles Select item 81395093. Isolation and characterization of proteoglycans . Hascall VC, Calabro A, Midura RJ, Yanagishita M. Methods Enzymol . 1994;230:390-417. No abstract available. PMID:  8139509

12. Similar articles Select item 36003254. Proteoglycans : isolation and purification from tissue cultures. Yanagishita M, Midura RJ, Hascall VC. Methods Enzymol . 1987;138:279-89. No abstract available. PMID:  3600325 Similar articles Select item 26957715. Specific activity of radiolabeled hexosamines in metabolic labeling experiments. Yanagishita M, Salustri A, Hascall VC. Methods Enzymol . 1989;179:435-45. No abstract available. PMID:  2695771 Similar articles Select item 29524496. Proteoglycan synthesis during intramembranous bone regeneration following avulsive wounding in guinea pig long bones. Freilich LS, Yanagishita M, Hascall VC. Connect Tissue Res. 1987;16(1):79-93. PMID:  2952449 Similar articles Select item 82982507. A brief history of proteoglycans .

13. Decorin Decorin is a small cellular or pericellular matrix proteoglycan and is closely related in structure to  biglycan  protein. Decorin and biglycan are thought to be the result of a  gene duplication . This protein is a component of  connective tissue , binds to  type I collagen   fibrils , and plays a role in  matrix  assembly. Decorin's name is a derivative of both the fact that it "decorates"  collagen type I , and that it interacts with the "d" and "e" bands of fibrils of this collagen. Decorin appears to influence  fibrillogenesis , and also interacts with  fibronectin ,  thrombospondin , the  complement component C1q ,  epidermal growth factor receptor  (EGFR) and transforming growth factor-beta ( TGF-beta ). Decorin has been shown to either enhance or inhibit the activity of  TGF-beta 1 . The primary function of decorin involves regulation during the  cell cycle . It has been involved in the regulation of  autophagy *, of  endothelial cell  and inhibits  angiogenesis **. This process is mediated by a high-affinity interaction with  VEGFR2  ( vascular endothelial growth factor receptor) which leads to increased levels of tumor suppressor gene called  PEG3 .  Other angiogenic growth factors that decorin inhibits are  angiopoietin , hepatocyte growth factor (HGF) and platelet-derived growth factor ( PDGF ). [7] Decorin has recently been established as a  myokine . In this role, it promotes muscle  hypertrophy  by binding with  myostatin

14. Terms * Autophagy   is the process involving  biochemical  events catalyzed by enzymes produced within the cell that leads to self-digestion. Autophagy  is a normal physiological process in the body that deals with destruction of cells in the body. It maintains homeostasis or normal functioning by protein degradation and turnover of the destroyed cell organelles for new cell formation. During cellular stress the process of  Autophagy  is upscaled and increased . ** Angiogenesis   is the physiological process through which new  blood vessels  form from pre-existing vessels.  In precise  usage  this is distinct from  vasculogenesis , which is the  de novo  formation  of  endothelial  cells from  mesoderm  cell precursors, [4]  and from  neovascularization , although discussions are not always precise (especially in older texts). The first vessels in the developing  embryo  form through vasculogenesis , after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease. ] Angiogenesis is a normal and vital process in growth and development, as well as in  wound healing  and in the formation of  granulation tissue . However, it is also a fundamental step in the transition of  tumors  from a benign state to a  malignant  one, leading to the use of  angiogenesis inhibitors  in the treatment of  cancer . The essential role of angiogenesis in tumor growth was first proposed in 1971 by  Judah Folkman , who described tumors as "hot and bloody," [6]  illustrating that, at least for many tumor types, flush  perfusion  and even  hyperemia  are characteristic.

15. Proteoglycans -Examples from daily Life

16. Examples

17. Schematic Structure of proteoglycans