Type

Journal Article

Authors

James S O'Donnell
Mike A Laffan
Roger J S Preston
Emily McRae
Virginie Terraube
Richard O'Kennedy
Barry Byrne
Thomas A J McKinnon
Rachel T McGrath

Subjects

Biochemistry

Topics
physiology protein processing post translational humans metabolism pharmacology biopolymers n acetylneuraminic acid von willebrand factor carbohydrate conformation chemistry cysteine proteases drug effects abo blood group system protein conformation collagen serine proteases galactose glycoside hydrolases adamts13 protein human substrate specificity adam proteins alpha n acetylgalactosaminidase peptide n4 n acetyl beta glucosaminyl asparagine neuraminidase

Expression of terminal alpha2-6-linked sialic acid on von Willebrand factor specifically enhances proteolysis by ADAMTS13. (2009)

Abstract von Willebrand factor (VWF) multimeric composition is regulated in plasma by ADAMTS13. VWF deglycosylation enhances proteolysis by ADAMTS13. In this study, the role of terminal sialic acid residues on VWF glycans in mediating proteolysis by ADAMTS13 was investigated. Quantification and distribution of VWF sialylation was examined by sequential digestion and high-performance liquid chromatography analysis. Total sialic acid expression on VWF was 167nmol/mg, of which the majority (80.1%) was present on N-linked glycan chains. Enzymatic desialylation of VWF by alpha2-3,6,8,9 neuraminidase (Neu-VWF) markedly impaired ADAMTS13-mediated VWF proteolysis. Neu-VWF collagen binding activity was reduced to 50% (+/- 14%) by ADAMTS13, compared with 11% (+/- 7%) for untreated VWF. Despite this, Neu-VWF exhibited increased susceptibility to other proteases, including trypsin, chymotrypsin, and cathepsin B. VWF expressing different blood groups exhibit altered ADAMTS13 proteolysis rates (O > or = B > A > or = AB). However, ABO blood group regulation of ADAMTS13 proteolysis was ablated on VWF desialylation, as both Neu-O-VWF and Neu-AB-VWF were cleaved by ADAMTS13 at identical rates. These novel data show that sialic acid protects VWF against proteolysis by serine and cysteine proteases but specifically enhances susceptibility to ADAMTS13 proteolysis. Quantitative variation in VWF sialylation therefore represents a key determinant of VWF multimeric composition and, as such, may be of pathophysiologic significance.
Collections Ireland -> Trinity College Dublin -> PubMed

Full list of authors on original publication

James S O'Donnell, Mike A Laffan, Roger J S Preston, Emily McRae, Virginie Terraube, Richard O'Kennedy, Barry Byrne, Thomas A J McKinnon, Rachel T McGrath

Experts in our system

1
James S O'Donnell
Trinity College Dublin
Total Publications: 57
 
2
Roger J S Preston
Trinity College Dublin
Total Publications: 32
 
3
R O'Kennedy
Dublin City University
Total Publications: 197
 
4
Barry Byrne
Dublin City University
Total Publications: 15