A1 Domain Required for Assembly of Von Willebrand Factor Tubules With in Vivo Helical Parameters

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In addition to its known activity in hemostasis, the A1 domain of the von Willebrand factor (VWF) glycoprotein plays a direct role in the assembly of VWF tubules for storage in Weibel-Palade bodies, according to a recent study published in Blood.

“It was previously observed that the presence of the A1 domain in recombinant VWF amino-terminal fragments led to more robust tubule formation in vitro and that the A1 domain was required for tubule formation in vivo,” the researchers explained in their report.

The team wanted to determine the structural basis for the discrepancy between the geometries of in vitro vs in vivo VWF tubules.


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They constructed in vitro VWF tubules containing different VWF protein domains, including the D1D2 propeptide, the D’D3 segment, the dimeric D’-A1 segment, the D’-A3 segment or the D’-C6 segment. segment. They also reconstituted the D1-A1 segment containing the R763G mutation, which keeps the propeptide covalently attached.

The researchers analyzed the tubules using cryogenic electron microscopy and compared those assessed in previous studies, consisting of the D1D2 and D’D3 segments, with the other tubules.

Using three-dimensional reconstructions after cryo-EM, the team found that the formation of tubules with the helical geometry observed for VWF in intracellular Weibel-Palade bodies requires the A1 domain, but not the A2 or A3 domains.

They reported that the tubules with and without the A1 domain appeared similar, but found that the A1 domain is inserted between helical turns of the tubule of the D assembly, replaces interhelical contacts, alters helical parameters, and leads to greater robustness of the tubule.

“In summary, we show that the VWF A1 domain is directly involved in the assembly and probably disassembly of the VWF tubules, complementing the known role of the A1 domain in post-secretory haemostasis,” the researchers conclude.

Reference

Javitt G, Yeshaya N, Khmelnitsky L, Fass D. Assembly of von Willebrand factor tubules with in vivo helical parameters requires insertion of the A1 domain. Blood. 2022;140(26):2835-2843. doi:10.1182/blood.2022017153

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