Cooperation of binding sites at the hydrophilic domain of cell-surface sulfatase Sulf1 allows for dynamic interaction of the enzyme with its substrate heparan sulfate

Milz, Fabian; Harder, Alexander; Neuhaus, Phillipp; Breitkreuz-Korff, Olga; Walhorn, Volker; Lübke, Torben; Anselmetti, Dario; Dierks, Thomas

doi:10.1016/j.bbagen.2013.07.014

Cited by 10 publications

(26 citation statements)

References 57 publications

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“…The recent models proposed for Sulf1 and Shh are particularly attractive and revealing. In the case of Sulf1, portions of the protein at the N- and C-termini would provide surfaces for interactions with CS-rich proteoglycans within the matrix, serving as a support and guiding system to allow the more centrally-located catalytic hydrophilic domain (HD) to act on the 6-O-sulfate substrate groups on neighboring HS chains and carry out sequential desulfation ( 48 ). In the case of Shh, the CW motif at the N-terminus would have a major role in binding to HS and signaling function, but the centrally-located Hh core GAG-binding site would be equally important for interactions with HS and CS and overall hedgehog protein distribution, structural features and function ( 11,40 ).…”

Section: Discussion and Prospectivementioning

confidence: 99%

“…Further structural and biochemical analyses using different Sulf1 deletion mutants showed that the interactions of Sulf1 with HS encompass a very large protein region called the hydrophilic domain (HD), spanning 319 amino acids Lys417-Lys735 ( 47 ). This large region includes a consensus HBD and when assayed in solution and solid phase binding assays, was found to bind HS with high affinity and specificity but not to CS, DS or 6-O-desulfated HS ( 48 ). HS/heparin binding was found to be mediated by 2 sites located in the inner and C-terminal regions of HD ( 48 ).…”

Section: More Complex Interactionsmentioning

confidence: 99%

“…This large region includes a consensus HBD and when assayed in solution and solid phase binding assays, was found to bind HS with high affinity and specificity but not to CS, DS or 6-O-desulfated HS ( 48 ). HS/heparin binding was found to be mediated by 2 sites located in the inner and C-terminal regions of HD ( 48 ). The authors concluded that the substrate specificity of Sulf1 is mediated by the HD, involves at least two separate HS-binding sites, and clearly depends on presence of 6-O sulfation, that is its own substrate.…”

Section: More Complex Interactionsmentioning

confidence: 99%

See 2 more Smart Citations

Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries

Billings

Pacifici

2015

Connective Tissue Research

123

145

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Heparan sulfate (HS) is a component of cell surface and matrix-associated proteoglycans (HSPGs) that collectively, play crucial roles in many physiologic processes including cell differentiation, organ morphogenesis and cancer. A key function of HS is to bind and interact with signaling proteins, growth factors, plasma proteins, immune-modulators and other factors. In so doing, the HS chains and HSPGs are able to regulate protein distribution, bio-availability and action on target cells and can also serve as cell surface co-receptors, facilitating ligand-receptor interactions. These proteins contain an HS/heparin-binding domain (HBD) that mediates their association and contacts with HS. HBDs are highly diverse in sequence and predicted structure, contain clusters of basic amino acids (Lys, Arg) and possess an overall net positive charge, most often within a consensus Cardin-Weintraub (CW) motif. Interestingly, other domains and residues are now known to influence protein-HS interactions, as well as interactions with other glycosaminoglycans, such as chondroitin sulfate. In this review we provide a description and analysis of HBDs in proteins including amphiregulin, fibroblast growth factor family members, heparanase, sclerostin and hedgehog protein family members. We discuss HBD structural and functional features and important roles carried out by other protein domains, and also provide novel conformational insights into the diversity of CW motifs present in Sonic, Indian and Desert hedgehogs. Finally, we review progress in understanding the pathogenesis of a rare pediatric skeletal disorder, Hereditary Multiple Exostoses (HME), characterized by HS deficiency and cartilage tumor formation. Advances in understanding protein-HS interactions will have broad implications for basic biology and translational medicine as well as for the development of HS-based therapeutics.

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Section: Discussion and Prospectivementioning

confidence: 99%

Section: More Complex Interactionsmentioning

confidence: 99%

Section: More Complex Interactionsmentioning

confidence: 99%

See 1 more Smart Citation

Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries

Billings

Pacifici

2015

Connective Tissue Research

123

145

View full text Add to dashboard Cite

show abstract

“…This model suggests that HSulf HD domain plays a major role in the enzyme activity and specificity and highlights the need of investigating further its interaction with HS. In this regard, Milz et al very recently showed that the HD domain indeed conferred HSulf specificity toward 6- O -sulfates and that it comprises at least two distinct HS-binding sites that allow for dynamic interaction with the polysaccharide (68). …”

Section: Sulfs: Extracellular Sulfatases Regulating Hs Structure and mentioning

confidence: 99%

“…Further investigation will be needed to determine whether residual binding could still influence HSulf-1 diffusion, and whether this applies similarly for HSulf-2. Lastly, Milz et al suggested that HSulf-1 could bind to CS/DS (68). As these GAGs are not suitable substrates for the enzyme, this interaction may limit diffusion of HSulf-1 throughout tissues.…”

Section: Sulfs In Cancer: Intriguing and Ambivalent Functionsmentioning

confidence: 99%

Post-Synthetic Regulation of HS Structure: The Yin and Yang of the Sulfs in Cancer

2014

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Heparan sulfate (HS) is a complex polysaccharide that takes part in most major cellular processes, through its ability to bind and modulate a very large array of proteins. These interactions involve saccharide domains of specific sulfation pattern (S-domains), the assembly of which is tightly orchestrated by a highly regulated biosynthesis machinery. Another level of structural control does also take place at the cell surface, where degrading enzymes further modify HS post-synthetically. Amongst them are the Sulfs, a family of extracellular sulfatases (two isoforms in human) that catalyze the specific 6-O-desulfation of HS. By targeting HS functional sulfated domains, Sulfs dramatically alter its ligand binding properties, thereby modulating a broad range of signaling pathways. Consequently, Sulfs play major roles during development, as well as in tissue homeostasis and repair. Sulfs have also been associated with many pathologies including cancer, but despite increasing interest, the role of Sulfs in tumor development still remains unclear. Studies have been hindered by a poor understanding of the Sulf enzymatic activities and conflicting data have shown either anti-oncogenic or tumor-promoting effects of these enzymes, depending on the tumor models analyzed. These opposite effects clearly illustrate the fine tuning of HS functions by the Sulfs, and the need to clarify the mechanisms involved. In this review, we will detail the present knowledge on the structural and functional properties of the Sulfs, with a special focus on their implication during tumor progression. Finally, we will discuss attempts and perspectives of using the Sulfs as a biomarker of cancer prognosis and diagnostic and as a target for anti-cancer therapies.

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Expression and purification of recombinant extracellular sulfatase HSulf-2 allows deciphering of enzyme sub-domain coordinated role for the binding and 6-O-desulfation of heparan sulfate

Seffouh

Masri

Makshakova

et al. 2019

Cell. Mol. Life Sci.

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Cooperation of binding sites at the hydrophilic domain of cell-surface sulfatase Sulf1 allows for dynamic interaction of the enzyme with its substrate heparan sulfate

Cited by 10 publications

References 57 publications

Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries

Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries

Post-Synthetic Regulation of HS Structure: The Yin and Yang of the Sulfs in Cancer

Expression and purification of recombinant extracellular sulfatase HSulf-2 allows deciphering of enzyme sub-domain coordinated role for the binding and 6-O-desulfation of heparan sulfate

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