title: Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix. Potential role of PACE4 in the activation of proproteins in the extracellular matrix.
abstract: PACE4, PC6 and furin are potent subtilisin-like proprotein convertases (SPCs) which are responsible for the activation of transforming growth factor-beta (TGFbeta)-related factors such as bone morphogenetic proteins. Heparan sulfate proteoglycan within the extracellular matrix (ECM) is known to regulate the biological activity of various differentiation factors including TGFbeta-related molecules. PACE4 binds tightly to heparin and its heparin-binding region was found to be a cationic stretch of amino acids between residues 743 and 760. Furthermore, PACE4 was detected in the extracellular material fraction of the HEK293 cells, defined as the material remaining on the culture plate following the removal of the cells from the plate. PACE4 bound to the extracellular fraction was selectively dislodged by heparin into the culture medium. Heparin has no inhibitory activity against PACE4. Similarly, PC6A is also able to bind to heparin, whereas soluble furin does not. In human placenta, PACE4 is mainly present in syncytiotrophoblasts and can be released by heparin. These results suggest that PACE4 and PC6 are unique SPC family proteases that anchor heparan sulfate proteoglycans at the ECM. The interaction between PACE4 and heparan sulfate proteoglycans might play an important role in the delicate spatiotemporal regulation of TGFbeta-related factors' biological activity.
authors.affiliation: Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, 2-1 Minamijosanjima, 770-8506, Tokushima, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuji
authors.forename: Kensuke
authors.initials: K
authors.lastname: Sakurai
authors.forename: Emi
authors.initials: E
authors.lastname: Kiyokage
authors.forename: Takahito
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Sizuyo
authors.initials: S
authors.lastname: Koide
authors.forename: Kazunori
authors.initials: K
authors.lastname: Toida
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ishimura
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Matsuda
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D010920:Placenta / Q000737:chemistry / Q000378:metabolism*; D045702:Proprotein Convertase 5; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D013381:Subtilisins / Q000378:metabolism*; D014327:Trophoblasts / Q000737:chemistry / Q000378:metabolism
chemical_list: D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; C080654:PCSK6 protein, human; D045702:Proprotein Convertase 5; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D013381:Subtilisins