HSPGs and PET

Heparan sulphate proteoglycans (HSPGs) are expressed and secreted by most, if not all, cells. Based on their core proteins, HSPGs are divided into several families. HSPGs are located on cell surfaces and in extracellular matrix (ECM), and can function as cell surface co-receptors. Membrane HSPGs can act as endocytic receptors, and some viruses, including SARS-CoV-2, utilize HSPGs for the attachment and internalization. Syndecans are HSPGs whose core proteins span the cell membrane. The core proteins of glypicans (GPCs) are anchored on the cell surface via GPI. Extracellular HSPGs include perlecan, betaglycan, and collagen XVIII. HSPGs such as serglycin are present in secretory vesicles.

Heparan sulphates (HS), belonging to glycosaminoglycans (GAGs), are linear polysaccharides with complex and variable sequences, and are synthesized as parts of HSPGs. Numerous enzymes are involved HS chain polymerization and modification, including sulphation/desulphation. Heparanase (HPSE) can selectively remove HS chains from HSPGs. Heparin, a natural anticoagulant, is a heparan sulphate, which is synthesized in mast cells.

Co-receptor functions of cell surface HSPGs include mediating initial binding of ligands, such as chemokines, facilitating, altering, or inhibiting signalling. HSPGs themselves do not possess intrinsic enzyme activities. HSPG co-receptors regulate cell adhesion, proliferation, migration, differentiation, and angiogenesis, and are involved in inflammation and tumour development. Therefore, HSPGs and HS are interesting targets for diagnostics and therapeutics.

Heparan sulphates are negatively charged, and the ligands and proteins that interact with the HS motifs have reciprocally charged HS-binding domain, HBD. HBDs are present on numerous plasma, ECM, and cell surface proteins. Negative charge of heparan sulphates attract cations such as 68Ga3+.

APACs

Antiplatelet and anticoagulants (APACs) are semisynthetic conjugates of a core protein and mast cell derived heparin proteoglycans. APACs have been labelled with 64Cu for PET/CT imaging (Tuuminen et al., 2017).

Osteosarcoma

[18F]FP-OSP-1 is a osteosarcoma specific peptide that shares homology with heparanase, binding to HSPGs (Sun et al., 2010).


See also:


Literature

Billings PC, Pacifici M. Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries. Connect Tissue Res. 2015; 56(4): 272-280. doi: 10.3109/03008207.2015.1045066.

De Pasquale V, Quiccione MS, Tafuri S, Avallone L, Pavone LM. Heparan sulfate proteoglycans in viral infection and treatment: a special focus on SARS-CoV-2. Int J Mol Sci. 2021; 22(12): 6574. doi: 10.3390/ijms22126574.

Hayashida K, Aquino RS, Park PW. Coreceptor functions of cell surface heparan sulfate proteoglycans. Am J Physiol Cell Physiol. 2022; 322(5): C896-C912. doi: 10.1152/ajpcell.00050.2022.

Rabenstein DL. Heparin and heparan sulfate: structure and function. Nat Prod Rep. 2002; 19(3): 312-331. doi: 10.1039/b100916h.

Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol. 2011; 3(7): a004952. doi: 10.1101/cshperspect.a004952.



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Updated at: 2023-01-31
Created at: 2023-01-30
Written by: Vesa Oikonen