A dominant negative splice variant of the heparan sulfate biosynthesis enzyme NDST1 reduces heparan sulfate sulfation.
NDST
alternative splicing
golgi enzyme
heparan sulfate biosynthesis
Journal
Glycobiology
ISSN: 1460-2423
Titre abrégé: Glycobiology
Pays: England
ID NLM: 9104124
Informations de publication
Date de publication:
23 05 2022
23 05 2022
Historique:
received:
22
02
2021
revised:
14
01
2022
accepted:
14
01
2022
pubmed:
10
2
2022
medline:
28
5
2022
entrez:
9
2
2022
Statut:
ppublish
Résumé
NDST1 (glucosaminyl N-deacetylase/N-sulfotransferase) is a key enzyme in heparan sulfate (HS) biosynthesis, where it is responsible for HS N-deacetylation and N-sulfation. In addition to the full length human enzyme of 882 amino acids, here designated NDST1A, a shorter form containing 825 amino acids (NDST1B) is synthesized after alternative splicing of the NDST1 mRNA. NDST1B is mostly expressed at a low level, but increased amounts are seen in several types of cancer where it is associated with shorter survival. In this study, we aimed at characterizing the enzymatic properties of NDST1B and its effect on HS biosynthesis. Purified recombinant NDST1B lacked both N-deacetylase and N-sulfotransferase activities. Interestingly, HEK293 cells overexpressing NDST1B synthesized HS with reduced sulfation and altered domain structure. Fluorescence resonance energy transfer-microscopy demonstrated that both NDST1A and NDST1B had the capacity to interact with the HS copolymerase subunits EXT1 and EXT2 and also to form NDST1A/NDST1B dimers. Since lysates from cells overexpressing NDST1B contained less NDST enzyme activity than control cells, we suggest that NDST1B works in a dominant negative manner, tentatively by replacing the active endogenous NDST1 in the enzyme complexes taking part in biosynthesis.
Identifiants
pubmed: 35137078
pii: 6523739
doi: 10.1093/glycob/cwac004
pmc: PMC9132247
doi:
Substances chimiques
Amino Acids
0
Heparitin Sulfate
9050-30-0
Sulfotransferases
EC 2.8.2.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
518-528Informations de copyright
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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