Structural characteristics of Heparan sulfate required for the binding with the virus processing Enzyme Furin

Abstract

Furin is one of the nine-member proprotein convertase family. Furin cleaves proteins with polybasic residues, which includes many viral glycoproteins such as SARS-Cov-2 spike protein. The cleavage is required for the activation of the proteins. Currently, the mechanisms that regulate Furin activity remain largely unknown. Here we demonstrated that Furin is a novel heparin/heparan sulfate binding protein by the use of biochemical and genetic assays. The K D is 9.78 nM based on the biolayer interferometry assay. Moreover, we found that sulfation degree, site-specific sulfation (N-sulfation and 3-O-sulfation), and iduronic acid are the major structural determinants for the binding. Furthermore, we found that heparin inhibits the enzymatic activity of Furin when pre-mixes heparin with either Furin or Furin substrate. We also found that the Furin binds with cells of different origin and the binding with the cells of lung origin is the strongest one. These data could advance our understanding of the working mechanism of Furin and will benefit the Furin based drug discovery such as inhibitors targeting the interaction between heparan sulfate and Furin for inhibition of viral infection. Supplementary information The online version contains supplementary material available at 10.1007/s10719-021-10018-8.

Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function

“…Clausen et al [108] corroborated this finding, demonstrating that binding of SARS-CoV-2 virion spike protein to eGCX HS promotes a conformational change in the spike protein receptor binding domain that enhances spike protein interactions with and anchoring to the endothelial surface ACE2 receptor. Moreover, furin availability for SARS-CoV-2 spike protein preactivation may depend on the presence of eGCX HS, specifically HS molecules rich in N- and 3-O-sulfation [88] . Notably, advanced age and underlying co-morbidities (e.g., obesity, hypertension) are considerable risk factors for severe SARS-CoV-2 infection [109] .…”