The propeptide of von Willebrand Factor independently mediates the assembly of von Willebrand multimers

Wise, Robert J.; Pittman, Debra D.; Handin, Robert I.; Kaufman, Randal J.; Orkin, Stuart H.

doi:10.1016/0092-8674(88)90511-9

Cited by 178 publications

(115 citation statements)

References 28 publications

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“…Recently, dimerization of MUC2 [48] was shown to be analogous to that of the von Willebrand factor to which the N-and C-terminal regions of MUC2 show some similarity [49,50]. von Willebrand factor has been shown to undergo proteolytic cleavage during its biosynthesis to yield a prepropetide, which in turn seems to play an important role in the oligomerization process [51]. Whether the 62 kDa molecular species recognized by mAb M75 is a putative link glycoprotein will require further molecular characterization.…”

Section: Discussionmentioning

confidence: 99%

Biochemical analysis of a bladder-cancer-associated mucin: structural features and epitope characterization

Bergeron

LaRue

Fradet

1997

Biochemical Journal

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Three monoclonal antibodies (mAbs), M344, M300 and M75, were shown to define a unique tumour-associated antigen (TAA) of superficial bladder tumours. The antigenic determinants are expressed on a very-high-molecular-mass component and, in about 50 % of the positive samples, one determinant is also detected on a 62 kDa molecular species, observed only under reducing conditions. The objectives of the present study were to characterize further this TAA by analysing (1) the biochemical nature of the epitopes recognized by the three mAbs, and (2) the biochemical and structural features of the molecule bearing them. The antigenicity was resistant to heat denaturation, trypsin and α-chymotrypsin treatments but highly sensitive to papain and Pronase digestion. NaIO % oxidation decreased reactivity to mAbs M344 and M300 but enhanced reactivity to mAb M75. The three determinants were insensitive to β-galactosidase and α--fucosidase but were sensitive to Vibrio cholerae neuraminidase.

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Section: Discussionmentioning

confidence: 99%

Biochemical analysis of a bladder-cancer-associated mucin: structural features and epitope characterization

Bergeron

LaRue

Fradet

1997

Biochemical Journal

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“…Experiments involving deletion of parts of VWFpp (⌬D1 and ⌬D2) or the entire VWFpp (⌬pro-VWF) demonstrated that deletion of these regions resulted in the expression of only the dimeric form of VWF and prevented the synthesis of VWF multimers. 9,27 When transfected in trans, the separate and noncontiguous VWFpp retains the ability to correctly orientate the mature-only subunits of ⌬pro-VWF to create multimers in vivo 27 and in vitro. 28 In patients with a heterozygous abnormality, the functional wild-type VWFpp is involved in multimerization of the wild-type VWF molecules and is unavailable to function in trans.…”

Section: Discussionmentioning

confidence: 99%

The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF

Rosenberg

Haberichter

Jozwiak

et al. 2002

Blood

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While studying patient plasma containing an unusual pattern of von Willebrand factor (VWF) multimers, we discovered a previously unreported phenomenon: heavy predominance of dimeric VWF. Genomic analysis revealed a new congenital mutation (Tyr87Ser) that altered the final stages of VWF biosynthesis. This mutation in the propeptide (VWFpp) resulted in synthesis of dimeric VWF with an almost complete loss of N-terminal multimerization. The multimer pattern in patient plasma appears to result from separate alleles' synthesizing wild-type or mutant (dimeric) VWF, with homodimers composing the predominant protomeric species. We have expressed VWF protein containing the Tyr87Ser mutation and analyzed the intracellular processing and resulting VWF biological functions. The expressed dimeric VWF displayed a loss of several specific functions: collagen binding, factor VIII binding, and ristocetin-induced platelet binding. However, granular storage of dimeric VWF was normal, demonstrating that the lack of multimerization does not preclude granular storage. Although the tertiary structure of the VWFpp remains unknown, the mutant amino acid is located in a region that is highly conserved across several species and may play a major role in the multimerization of VWF. Our data suggest that one function of the highly cysteine-rich VWFpp is to align the adjacent subunits of VWF into the correct configuration, serving as an intramolecular chaperone. The integrity of the VWFpp is essential to maintain the proper spacing and alignment of the multiple cysteines in the VWFpp and N-terminus of the mature

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“…3 and 4). These cleavages remove propeptides that function in a variety of essential roles in the maturation of the precursor proteins including (i) correct folding and disulfide bond formation (5,6), (ii) y-carboxylation of glutamic acid residues (7,8), (iii) directing intracellular targeting (9), and (iv) regulating the coordinate synthesis of multiple mature peptides from a single precursor polypeptide, typified by proopiomelanocortin (10,11). In addition to these natural cellular products, several viral polyproteins require cleavage at paired basic amino acid residues.…”

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confidence: 99%

Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site.

Wise¹,

Barr²,

Wong³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

283

176

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Intracellular proteolytic processing of precursor polypeptides is an essential step in the maturation of many proteins, including plasma proteins, hormones, neuropeptides, and growth factors. Most frequently, propeptide cleavage occurs after paired basic amino acid residues. To date, no mammalian propeptide processing enzyme with such specificity has been purified or cloned and functionally characterized. We report the isolation and functional expression of a cDNA encoding a propeptide-cleaving enzyme from a human liver cell line. The encoded protein, called PACE (paired basic amino acid cleaving enzyme), has structural homology to the well-characterized subtilisin-like protease Kex2 from yeast.The functional specificity of PACE for mediating propeptide cleavage at paired basic amino acid residues was demonstrated by the enhancement of propeptide processing of human von Willebrand factor when coexpressed with PACE in COS-1 cells.

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The propeptide of von Willebrand Factor independently mediates the assembly of von Willebrand multimers

Cited by 178 publications

References 28 publications

Biochemical analysis of a bladder-cancer-associated mucin: structural features and epitope characterization

Biochemical analysis of a bladder-cancer-associated mucin: structural features and epitope characterization

The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF

Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site.

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