Distribution and Evolution of vonWillebrand/Integrin A Domains: Widely Dispersed Domainswith Roles in Cell Adhesion and Elsewhere

摘要

The von Willebrand A (VWA) domain is a well-studied domain involved in cell adhesion, in extracellular matrix proteins, and in integrin receptors. A number of human diseases arise from mutations in VWA domains. We have analyzed the phylogenetic distribution of this domain and the relationships among ∼500 proteins containing this domain. Although the majority of VWA-containing proteins are extracellular, the most ancient ones, present in all eukaryotes, are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport, and the proteasome. A common feature seems to be involvement in multiprotein complexes. Subsequent evolution involved deployment of VWA domains by Metazoa in extracellular proteins involved in cell adhesion such as integrin β subunits (all Metazoa). Nematodes and chordates separately expanded their complements of extracellular matrix proteins containing VWA domains, whereas plants expanded their intracellular complement. Chordates developed VWA-containing integrin α subunits, collagens, and other extracellular matrix proteins(e.g., matrilins, cochlin/vitrin, and von Willebrand factor).Consideration of the known properties of VWA domains inintegrins and extracellular matrix proteins allows insightsinto their involvement in protein–protein interactions and the rolesof bound divalent cations and conformational changes. These allowinferences about similar functions in novel situations such as proteaseregulators (e.g., complement factors and trypsin inhibitors) andintracellular proteins (e.g., helicases, chelatases, and copines).