title: The principal neuronal gD-type 3-O-sulfotransferases and their products in central and peripheral nervous system tissues.
abstract: Within the nervous system, heparan sulfate (HS) of the cell surface and extracellular matrix influences developmental, physiologic and pathologic processes. HS is a functionally diverse polysaccharide that employs motifs of sulfate groups to selectively bind and modulate various effector proteins. Specific HS activities are modulated by 3-O-sulfated glucosamine residues, which are generated by a family of seven 3-O-sulfotransferases (3-OSTs). Most isoforms we herein designate as gD-type 3-OSTs because they generate HS(gD+), 3-O-sulfated motifs that bind the gD envelope protein of herpes simplex virus 1 (HSV-1) and thereby mediate viral cellular entry. Certain gD-type isoforms are anticipated to modulate neurobiologic events because a Drosophila gD-type 3-OST is essential for a conserved neurogenic signaling pathway regulated by Notch. Information about 3-OST isoforms expressed in the nervous system of mammals is incomplete. Here, we identify the 3-OST isoforms having properties compatible with their participation in neurobiologic events. We show that 3-OST-2 and 3-OST-4 are principal isoforms of brain. We find these are gD-type enzymes, as they produce products similar to a prototypical gD-type isoform, and they can modify HS to generate receptors for HSV-1 entry into cells. Therefore, 3-OST-2 and 3-OST-4 catalyze modifications similar or identical to those made by the Drosophila gD-type 3-OST that has a role in regulating Notch signaling. We also find that 3-OST-2 and 3-OST-4 are the predominant isoforms expressed in neurons of the trigeminal ganglion, and 3-OST-2/4-type 3-O-sulfated residues occur in this ganglion and in select brain regions. Thus, 3-OST-2 and 3-OST-4 are the major neural gD-type 3-OSTs, and so are prime candidates for participating in HS-dependent neurobiologic events.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Lawrence
authors.forename: Tomio
authors.initials: T
authors.lastname: Yabe
authors.forename: Sassan
authors.initials: S
authors.lastname: Hajmohammadi
authors.forename: John
authors.initials: J
authors.lastname: Rhodes
authors.forename: Melissa
authors.initials: M
authors.lastname: McNeely
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Edward D
authors.initials: ED
authors.lastname: Lamperti
authors.forename: Paul A
authors.initials: PA
authors.lastname: Toselli
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Lech
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Spear
authors.forename: Robert D
authors.initials: RD
authors.lastname: Rosenberg
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Shworak
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D016466:CHO Cells; D002490:Central Nervous System / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006497:Heparan Sulfate / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000502:physiology; D006801:Humans; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D017933:Peripheral Nervous System / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D006497:Heparan Sulfate; D007527:Isoenzymes; D015238:Sulfotransferases; C021350:heparitin sulfotransferase