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Sialic acid prevents loss of large von Willebrand factor multimers by
protecting against amino-terminal proteolytic cleavage
SD Berkowitz and AB Federici
Department of Basic and Clinical Research, Research Institute of Scripps
Clinic, La Jolla, CA.
Removal of sialic acid from the von Willebrand factor (vWF) subunit exposes
additional cleavage sites in the amino-terminal region that are associated
with loss of large multimers. The extent of large multimer loss was
evaluated by examining the sites of subunit cleavage of native and
carbohydrate-modified vWF after treatment with trypsin, chymotrypsin, or
plasmin. In the presence of proteinase inhibitors, purified vWF was treated
with neuraminidase alone to remove 90% to 95% of the sialic acid or with
neuraminidase and beta-galactosidase to remove the sialic acid and 45% to
50% of the D-galactose, with little or no loss of large multimers observed.
Digestion of native vWF with trypsin produced the greatest loss of large
multimers, while chymotrypsin produced less and plasmin produced the least.
Large multimer loss was more extensive with each enzyme after carbohydrate
modification of vWF. The extent and approximate location of subunit
cleavage was determined by immunoblotting and monoclonal antibody epitope
mapping. Trypsin, chymotrypsin, and plasmin were shown to produce both
amino- and carboxyl-terminal fragments. The number, location, and relative
quantities of carboxyl-terminal fragments produced were unchanged after
carbohydrate modification. However, digestion of the amino-terminal region
was considerably more extensive after carbohydrate modification as judged
by a marked decrease or absence of the larger fragments seen when native
vWF was digested, and by the appearance of new smaller molecular mass
species. Therefore, the greater loss of large multimers that occurs after
carbohydrate modification is likely to be the result of cleavages in the
amino- terminal region of the molecule. By protecting the vWF subunit
against amino-terminal cleavage, sialic acid inhibits the loss of large
multimers.
Volume 72,
Issue 5,
pp. 1790-1796,
11/01/1988
Copyright © 1988 by The American Society of Hematology
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