Distribution and Evolution of von Willebrand/Integrin A Domains: Widely Dispersed Domains with Roles in Cell Adhesion and Elsewhere

Abstract

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 approximately 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 beta 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 alpha subunits, collagens, and other extracellular matrix proteins (e.g., matrilins, cochlin/vitrin, and von Willebrand factor). Consideration of the known properties of VWA domains in integrins and extracellular matrix proteins allows insights into their involvement in protein-protein interactions and the roles of bound divalent cations and conformational changes. These allow inferences about similar functions in novel situations such as protease regulators (e.g., complement factors and trypsin inhibitors) and intracellular proteins (e.g., helicases, chelatases, and copines).

Copine-I represses NF-κB transcription by endoproteolysis of p65

“…All b2 integrins form a functional heterodimer complex with integrin a subunits that recognize ligand binding via the vWA domain (Dickeson and Santoro, 1998). It is the vWA domains of the integrin subunits that show significant homology with the copine-I AD (Whittaker and Hynes, 2002). Therefore, perhaps one of the evolutionarily conserved functions of vWA domains is to associate with protease-containing protein complexes.…”

“…The C2Ds of copines contain aspartate residues important for calcium and phospholipid binding (Nalefski and Falke, 1996;Rizo and Sudhof, 1998). The AD shows similarity to proteins that contain the von Willebrand factor (vWF) domain referred to as the vWF A domain (vWA) protein superfamily (Whittaker and Hynes, 2002). Although the majority of vWA-containing proteins in higher eukaryotes is extracellular, the most evolutionally conserved vWA domains are intracellular proteins.…”

Insight into interactions of the von-Willebrand-factor-A-like domain 2 with the FNIII-like domain 9 of collagen VII by NMR and SPR

“…In contrast the N-terminal non-collagenous domain 1 (NC-1) consists of several subdomains with high homologies to adhesion proteins. The C-terminal subdomain of NC-1 reveals high homology to von-Willebrand-factor A and is called von-Willebrand-factor-A like domain 2 (vWFA2) [3]. A schematic representation of a single Col7 a-chain forming a homotrimer is shown in Investigations have shown that vWFA2 plays a crucial role for binding to type I collagen but also for interactions with other components of the extracellular matrix [2,4].…”

“…Based on NMR resonance assignment secondary structure elements have Abbreviations: Col7, type VII collagen; EBA, epidermolysis bullosa acquisita; mFNIII-9, murine fibronectin-III-like domain 9; NC-1, non-collagenous domain 1; NMR, nuclear magnetic resonance; SPR, surface plasmon resonance; TALOS, torsion angle likelihood obtained from shift and sequence similarity; mvWFA2, murine von-Willebrand-factor-A-like domain 2; TSP-d 4 , 3-(trimethylsilyl)propionic acid-d 4 sodium salt been obtained with the program torsion angle likelihood obtained from shift and sequence similarity+ (TALOS)+ [9]. Additional information has been achieved by 3 J-H(N)-H(a)-coupling constants and hydrogen-deuterium exchange. The experimental data are in good agreement with a homology model.…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…In addition, the expression of α 2 δ-4 subunit, encoded by C ACNA2D4 , is mostly copious in non-neuronal cells apart from retinal neurons [36,37]. By bioinformatics, the proteins encoded by several other genes have been identified, and they share the similar structure with α 2 δ subunits [38], but have not been proved to function as calcium α 2 δ subunits. The α 2 δ-1 subunit plays a vital role in hypertensive vascular Ca V 1.2 channel properties [39,40].…”