Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor.

Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Research Abstract Details 

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Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Abstract Text:

Jing-Jiang Wu,Kazuo Fujikawa,Brad A McMullen,Dominic W Chung,

ADAMTS-13, a metalloprotease in plasma, specifically cleaves the Tyr-1605-Met-1606 bond in the A2 domain of von Willebrand factor (VWF) to regulate the polymer distribution of VWF in circulation, which is critical for primary hemostasis. A 73-aa peptide (VWF73) was previously identified as the minimal substrate cleavable by ADAMTS-13. In this study, VWF73 was enzymatically and chemically cleaved into shorter peptides, and the inhibition of cleavage of a VWF73-derived substrate by these purified peptides was measured in competition studies using a quantitative assay we recently reported. A 24-aa peptide encompassing Pro-1645-Lys-1668 (P'40-P'63) and situated 40 aa downstream from the cleavage site was the minimal peptide that could bind to and competitively inhibit ADAMTS-13 (K(i) = 12 microM). This peptide and longer peptides encompassing this core sequence also inhibited the cleavage of multimeric VWF by ADAMTS-13. These results suggest the presence of a complementary extended binding site, or exosite, on ADAMTS-13. Mutation of Asp-1653 and Asp-1663 to Ala in this region significantly reduced the rate of cleavage of the substrate peptide, whereas the Glu1655Ala mutation caused an enhanced rate of cleavage. These results suggest that ionic interactions of the Pro-1645-Lys-1668 region with the exosite on ADAMTS-13 play a significant role in mediating substrate recognition.

Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Publishing Authors By Initials

JJ Wu,K Fujikawa,BA McMullen,DW Chung,

For similar proteins: blood proteins: blood coagulation factors: von willebrand factor research abstracts see: proteins: blood proteins: blood coagulation factors: von willebrand factor research

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Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 103

Page Numbers: 18470-4

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 22

MONTH: 11

YEAR: 2006

Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Keywords Mesh Terms:

KEYWORDS: von Willebrand Factor

MESH TERMS: metabolism

Chemical & Substance for Abstract: Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Information

Substance Name: ADAMTS13 protein, human

Registry Number: EC 3.4.24.-

Grant and Affiliation Information for Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor.

AFFILIATION: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL 070681

ACRONYM: HL

MEDLINETA: Proc Natl Acad Sci U S A

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