VWD domain stabilization by autocatalytic Asp-Pro cleavage

Noa Yeshaya, Prashant Kumar Gupta, Orly Dym, David Morgenstern, Dan Thomas Major, Deborah Fass

Research output: Contribution to journalArticlepeer-review


Domains known as von Willebrand factor type D (VWD) are found in extracellular and cell-surface proteins including von Willebrand factor, mucins, and various signaling molecules and receptors. Many VWD domains have a glycine-aspartate-proline-histidine (GDPH) amino-acid sequence motif, which is hydrolytically cleaved post-translationally between the aspartate (Asp) and proline (Pro). The Fc IgG binding protein (FCGBP), found in intestinal mucus secretions and other extracellular environments, contains 13 VWD domains, 11 of which have a GDPH cleavage site. In this study, we investigated the structural and biophysical consequences of Asp-Pro peptide cleavage in a representative FCGBP VWD domain. We found that endogenous Asp-Pro cleavage increases the resistance of the domain to exogenous proteolytic degradation. Tertiary structural interactions made by the newly generated chain termini, as revealed by a crystal structure of an FCGBP segment containing the VWD domain, may explain this observation. Notably, the Gly-Asp peptide bond, upstream of the cleavage site, assumed the cis configuration in the structure. In addition to these local features of the cleavage site, a global organizational difference was seen when comparing the FCGBP segment structure with the numerous other structures containing the same set of domains. Together, these data illuminate the outcome of GDPH cleavage and demonstrate the plasticity of proteins with VWD domains, which may contribute to their evolution for function in a dynamic extracellular environment.

Original languageEnglish
Article numbere4929
JournalProtein Science
Issue number3
StatePublished - Mar 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.


This work was supported by the Israel Science Foundation (grant 2204/23 to DF) and the European Research Council (grant 101097867 to DF).

FundersFunder number
European Research Council101097867
Israel Science Foundation2204/23


    • Asp-Pro bond
    • cis peptide
    • domain stability
    • mucus
    • multi-domain protein
    • proteolysis


    Dive into the research topics of 'VWD domain stabilization by autocatalytic Asp-Pro cleavage'. Together they form a unique fingerprint.

    Cite this