Glycoconjugate Journal

, Volume 35, Issue 4, pp 387–396 | Cite as

Heparan sulfate S-domains and extracellular sulfatases (Sulfs): their possible roles in protein aggregation diseases

  • Kazuchika Nishitsuji


Highly sulfated domains of heparan sulfate (HS), also known as HS S-domains, consist of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)–]. The expression of HS S-domains at the cell surface is determined by two mechanisms: tightly regulated biosynthetic machinery and enzymatic remodeling by extracellular endoglucosamine 6-sulfatases, Sulf-1 and Sulf-2. Intracellular or extracellular deposits of misfolded and aggregated proteins are characteristic of protein aggregation diseases. Although proteins can aggregate alone, deposits of protein aggregates in vivo contain a number of proteinaceous and non-protein components. HS S-domains are one non-protein component of these aggregated deposits. HS S-domains are considered to be critical for signal transduction of several growth factors and several disease conditions, such as tumor progression, but their roles in protein aggregation diseases are not yet fully understood. This review summarizes the current understanding of the possible roles of HS S-domains and Sulfs in the formation and cytotoxicity of protein aggregates.


Protein aggregation disease Amyloidosis Amyloid Glycosaminoglycan Heparan sulfate Sulf Sulfatase 


Amyloid β protein


Heparan sulfate




Alzheimer’s disease


Amyloid A


Serum amyloid protein A


Amyloid immunoglobulin light chain




Amyloid transthyretin


Islet amyloid polypeptide


Heparan sulfate proteoglycan




Glucuronic acid


Iduronic acid


Fibroblast growth factor


Vascular endothelial growth factor


Glial cell line-derived neurotrophic factor


Apolipoprotein A-I



The author thanks Dr. Kenji Uchimura for critical reading and comments on the manuscript. The author would like to apologize to those whose work could not be directly cited because of space constraints. This work was partly supported by Grants-in-Aid for Young Scientists B-15 K19488 and B-17 K16123 from the Japan Society for the Promotion of Science.

Compliance with ethical standards

Conflicts of interest

Kazuchika Nishitsuji declares no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiochemistryWakayama Medical UniversityWakayamaJapan
  2. 2.Department of Pathology and Laboratory Medicine, Graduate School of Biomedical SciencesTokushima UniversityTokushimaJapan

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