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Complement and the multifaceted functions of VWA and integrin I domains

Timothy A Springer1

  • 1CBR Institute for Biomedical Research and Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA. springeroffice@cbr.med.harvard.edu

Structure (London, England : 1993)
|November 14, 2006
PubMed

Insights

The VWA domain in complement protein C2 undergoes a unique conformational change upon activation, distinct from other known VWA domains. This structural plasticity impacts its function in various biological processes.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Immunology

Background:

  • The von Willebrand factor type A (VWA) domain is a conserved protein module found in numerous proteins involved in diverse biological processes.
  • The complement system is a critical part of innate immunity, and its proper functioning relies on the precise regulation of its protein components.

Purpose of the Study:

  • To analyze the structural differences between the zymogen C2 and its activated form, C2a, focusing on the VWA domain.
  • To review the conformational diversity and ligand-binding properties of VWA domains across various biological contexts.
  • To discuss the implications of these findings for the stability of complement convertases.

Main Methods:

  • X-ray crystallography to determine the structure of complement protein component C2a.
  • Comparative structural analysis of VWA domains from different proteins.
  • Literature review on VWA domain function and regulation.

Main Results:

  • The crystal structure of C2a reveals a novel interface between its VWA and serine protease domains, absent in zymogen C2.
  • The conformational change in the C2 VWA domain differs significantly from those observed in other VWA domains, such as integrin I domains.
  • VWA domains exhibit remarkable diversity in conformational regulation and ligand binding across complement, hemostasis, cell adhesion, and other pathways.

Conclusions:

  • The unique conformational plasticity of the C2 VWA domain is crucial for complement activation.
  • Understanding VWA domain diversity provides insights into their roles in various cellular functions.
  • The structural insights into C2a may inform strategies for modulating complement system activity.

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