Heparan sulfate biosynthesis: regulation and variability - PubMed (original) (raw)

Review

Heparan sulfate biosynthesis: regulation and variability

Johan Kreuger et al. J Histochem Cytochem. 2012 Dec.

Abstract

Nearly all vertebrate cells have been shown to express heparan sulfate proteoglycans (HSPGs) at the cell surface. The HSPGs bind to many secreted signaling proteins, including numerous growth factors, cytokines, and morphogens, to affect their tissue distribution and signaling. The heparan sulfate (HS) chains may have variable length and may differ with regard to both degree and pattern of sulfation. As the sulfation pattern of HS chains in most cases will determine if an interaction with a potential ligand will take place, as well as the affinity of the interaction, a key to understanding the function of HSPGs is to clarify how HS biosynthesis is regulated in different biological contexts. This review provides an introduction to the current understanding of HS biosynthesis and its regulation, and identifies research areas where more knowledge is needed to better understand how the HS biosynthetic machinery works.

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Conflict of interest statement

Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.

Heparan sulfate (HS) structure and biosynthesis scheme. Shown is a simplified scheme outlining the different steps of HS biosynthesis involving specific enzymes or enzyme families. The structure of HS is variable, and a hypothetical example is shown. The saccharide units corresponding to symbols used are defined below the scheme. The abbreviations related to structure are as follows: NS, _N_-sulfated GlcN; 6S, 6-_O_-sulfated GlcN; 2S, 2-_O_-sulfated IdoA; 3S, 3-_O_-sulfated GlcN; Ser, serine. For additional information, see Figure 2 and the main text.

Figure 2.

Formation and fate of heparan sulfate (HS). The formation of HS takes place in the Golgi network, where most of the biosynthetic enzymes are anchored to the Golgi membrane. Biosynthetic precursors (3′-phosphoadenosine-5′-phosphosulfate [PAPS] and UDP-sugars) are formed in the cytosol and transported into the Golgi. Prior to HS polymerization, the linkage region is formed attached to a serine residue in a core protein. Next, the EXT1/EXT2 polymerase complex adds alternating units of GlcNAc and GlcA to the non-reducing end of the growing chain (arrow a indicates the direction of polymerization). The polymerization is followed by a series of modification reactions, likely to begin with_N_-deacetylation/_N_-sulfation, followed by epimerization and 2-_O_-sulfation, and finally 6-_O_- and 3-_O_-sulfation. Notably, it has recently been proposed that the direction of _N_-deacetylation/_N_-sulfation is opposite to that of polymerization (arrow b). Known interactions between enzymes are indicated, but additional protein interactions as well as larger GAGosome complexes encompassing many enzymes may exist. After completion of the modification process, the core proteins are transported to the cell membrane, where they are exocytosed. HS chains of both membrane-intercalated and secreted proteoglycans (PGs) can be trimmed by the actions of heparanase and endosulfatases, and surface-bound PGs can also be shed. Finally, endocytosis of PGs leads to degradation of HS by exoenzymes in lysosomes or, alternatively, to recycling and possibly additional rounds of HS biosynthesis/modification onto recycled core proteins. Some regulatory steps (Reg.) during the biosynthetic process are indicated.

References

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Heparan sulfate biosynthesis: regulation and variability - PubMed (original) (raw)