VWA

von Willebrand factor (vWF) type A domain

• SMART accession number: SM00327
• Description: VWA domains in extracellular eukaryotic proteins mediate adhesion via metal ion-dependent adhesion sites (MIDAS). Intracellular VWA domains and homologues in prokaryotes have recently been identified. The proposed VWA domains in integrin beta subunits have recently been substantiated using sequence-based methods.
• Interpro abstract (IPR002035):

  The von Willebrand factor is a large multimeric glycoprotein found in blood plasma. Mutant forms are involved in the aetiology of bleeding disorders [(PUBMED:8440408)]. In von Willebrand factor, the type A domain (vWF) is the prototype for a protein superfamily. The vWF domain is found in various plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins [(PUBMED:8412987), (PUBMED:8145250), (PUBMED:1864378)]. 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 appears to be involvement in multiprotein complexes. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands [(PUBMED:8412987)]. A number of human diseases arise from mutations in VWA domains.

  Secondary structure prediction from 75 aligned vWF sequences has revealed a largely alternating sequence of alpha-helices and beta-strands [(PUBMED:8145250)]. The vWF domain fold is predicted to be a doubly-wound, open, twisted beta-sheet flanked by alpha-helices [(PUBMED:7843416)]. 3D structures have been determined for the I-domains of integrins CD11b (with bound magnesium) [(PUBMED:7867070)] and CD11a (with bound manganese) [(PUBMED:7479767)]. The domain adopts a classic alpha/beta Rossmann fold and contains an unusual metal ion coordination site at its surface. It has been suggested that this site represents a general metal ion-dependent adhesion site (MIDAS) for binding protein ligands [(PUBMED:7867070)]. The residues constituting the MIDAS motif in the CD11b and CD11a I-domains are completely conserved, but the manner in which the metal ion is coordinated differs slightly [(PUBMED:7479767)].

• GO function: protein binding (GO:0005515)

There are 15246 VWA domains in 13014 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Binding / catalysis: Divalent cations.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Ponting CP, Aravind L, Schultz J, Bork P, Koonin EV
• Eukaryotic signalling domain homologues in archaea and bacteria. Ancient ancestry and horizontal gene transfer.
• J Mol Biol. 1999; 289: 729-45

Phyletic distributions of eukaryotic signalling domains were studied using recently developed sensitive methods for protein sequence analysis, with an emphasis on the detection and accurate enumeration of homologues in bacteria and archaea. A major difference was found between the distributions of enzyme families that are typically found in all three divisions of cellular life and non-enzymatic domain families that are usually eukaryote-specific. Previously undetected bacterial homologues were identified for# plant pathogenesis-related proteins, Pad1, von Willebrand factor type A, src homology 3 and YWTD repeat-containing domains. Comparisons of the domain distributions in eukaryotes and prokaryotes enabled distinctions to be made between the domains originating prior to the last common ancestor of all known life forms and those apparently originating as consequences of horizontal gene transfer events. A number of transfers of signalling domains from eukaryotes to bacteria were confidently identified, in contrast to only a single case of apparent transfer from eukaryotes to archaea.

• Baldwin ET et al.
• Cation binding to the integrin CD11b I domain and activation model assessment.
• Structure. 1998; 6: 923-35

BACKGROUND: The integrin family of cell-surface receptors mediate cell adhesion through interactions with the extracellular matrix or other cell-surface receptors. The alpha chain of some integrin heterodimers includes an inserted 'I domain' of about 200 amino acids which binds divalent metal ions and is essential for integrin function. Lee et al. proposed that the I domain of the integrin CD11b adopts a unique 'active' conformation when bound to its counter receptor. In addition, they proposed that the lack of adhesion in the presence of Ca2+ ion reflected the stabilization of an 'inactive' I-domain conformation. We set out to independently determine the structure of the CD11 b I domain and to evaluate the structural effects of divalent ion binding to this protein. RESULTS: We have determined the X-ray structure of a new crystal form of the CD11 b I domain in the absence of added metal ions by multiple isomorphous replacement (MIR). Metal ions were easily introduced into this crystal form allowing the straight-forward assessment of the structural effects of divalent cation binding at the metal ion dependent adhesion site (MIDAS). The equilibrium binding constants for these ions were determined by titration calorimetry. The overall protein conformation and metal-ion coordination of the I domain is the same as that observed for all previously reported CD11 a I-domain structures and a CD11 b I-domain complex with Mn2+. These structures define a majority conformation. CONCLUSIONS: Addition of the cations Mg2+, Mn2+ and Cd2+ to the metal-free I domain does not induce conformational changes in the crystalline environment. Moreover, we find that Ca2+ binds poorly to the I domain which serves to explain its failure to support adhesion. We show that the active conformation proposed by Lee et al, is likely to be a construct artifact and we propose that the currently available data do not support a dramatic structural transition for the I domain during counter-receptor binding.

• Sadler JE
• Biochemistry and genetics of von Willebrand factor.
• Annu Rev Biochem. 1998; 67: 395-424

Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis, and deficiency of VWF, or von Willebrand disease (VWD), is the most common inherited bleeding disorder. VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. These activities appear to be regulated by allosteric mechanisms and possibly by hydrodynamic shear forces. VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. VWF is assembled from identical approximately 250 kDa subunits into disulfide-linked multimers that may be > 20,000 kDa. Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites. This growing body of information about VWF synthesis, structure, and function has allowed the reclassification of VWD based upon distinct pathophysiologic mechanisms that appear to correlate with clinical symptoms and the response to therapy.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the VWA domain.

Protein	Disease
Collagen alpha-1(VII) chain (Q02388) (SMART)	OMIM:120120: Epidermolysis bullosa dystrophica, dominant OMIM:131750: Epidermolysis bullosa dystrophica, recessive OMIM:226600: Epidermolysis bullosa, pretibial, dominant and recessive OMIM:131850:
Collagen alpha-3(VI) chain (P12111) (SMART)	OMIM:120250: Bethlem myopathy OMIM:158810:
von Willebrand antigen 2 (P04275) (SMART)	OMIM:193400: von Willebrand disease

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
16.10	map04810	Regulation of actin cytoskeleton
14.88	map00860	Porphyrin and chlorophyll metabolism
14.75	map04510	Focal adhesion
14.75	map04512	ECM-receptor interaction
5.68	map04514	Cell adhesion molecules (CAMs)
4.19	map04670	Leukocyte transendothelial migration
3.92	map04640	Hematopoietic cell lineage
3.52	map04740	Olfactory transduction
3.11	map03022	Basal transcription factors
2.98	map04010	MAPK signaling pathway
2.71	map00910	Nitrogen metabolism
2.57	map05222	Small cell lung cancer
2.44	map04610	Complement and coagulation cascades
2.30	map03050	Proteasome
2.03	map04650	Natural killer cell mediated cytotoxicity
1.49	map04360	Axon guidance
0.95	map03090	Type II secretion system
0.41	map00562	Inositol phosphate metabolism
0.41	map04070	Phosphatidylinositol signaling system
0.27	map00440	Aminophosphonate metabolism
0.27	map00900	Terpenoid biosynthesis
0.14	map00730	Thiamine metabolism
0.14	map00230	Purine metabolism

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with VWA domain which could be assigned to a KEGG orthologous group, and not all proteins containing VWA domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of VWA domains in PDB

PDB code	Title
1ao3	A3 domain of von willebrand factor
1aox	I domain from integrin alpha2-beta1
1atz	Human von willebrand factor a3 domain
1auq	A1 domain of von willebrand factor
1bho	Mac-1 i domain magnesium complex
1bhq	Mac-1 i domain cadmium complex
1ck4	Crystal structure of rat a1b1 integrin i-domain.
1cqp	Crystal structure analysis of the complex lfa-1 (cd11a) i- domain / lovastatin at 2.6 a resolution
1dgq	Nmr solution structure of the inserted domain of human leukocyte function associated antigen-1
1dzi	Integrin alpha2 i domain / collagen complex
1fe8	Crystal structure of the von willebrand factor a3 domain in complex with a fab fragment of igg ru5 that inhibits collagen binding
1fns	Crystal structure of the von willebrand factor (vwf) a1 domain i546v mutant in complex with the function blocking fab nmc4
1idn	Mac-1 i domain metal free
1ido	I-domain from integrin cr3, mg2+ bound
1ijb	The von willebrand factor mutant (i546v) a1 domain
1ijk	The von willebrand factor mutant (i546v) a1 domain- botrocetin complex
1jeq	Crystal structure of the ku heterodimer
1jey	Crystal structure of the ku heterodimer bound to dna
1jlm	I-domain from integrin cr3, mn2+ bound
1jv2	Crystal structure of the extracellular segment of integrin alphavbeta3
1l5g	Crystal structure of the extracellular segment of integrin avb3 in complex with an arg-gly-asp ligand
1lfa	Cd11a i-domain with bound mn++
1m10	Crystal structure of the complex of glycoprotein ib alpha and the von willebrand factor a1 domain
1m1u	An isoleucine-based allosteric switch controls affinity and shape shifting in integrin cd11b a-domain
1m1x	Crystal structure of the extracellular segment of integrin alpha vbeta3 bound to mn2+
1m2o	Crystal structure of the sec23-sar1 complex
1m2v	Crystal structure of the yeast sec23/24 heterodimer
1mf7	Integrin alpha m i domain
1mhp	Crystal structure of a chimeric alpha1 integrin i-domain in complex with the fab fragment of a humanized neutralizing antibody
1mjn	Crystal structure of the intermediate affinity al i domain mutant
1mq8	Crystal structure of alphal i domain in complex with icam-1
1mq9	Crystal structure of high affinity alphal i domain with ligand mimetic crystal contact
1mqa	Crystal structure of high affinity alphal i domain in the absence of ligand or metal
1n3y	Crystal structure of the alpha-x beta2 integrin i domain
1n9z	Integrin alpha m i domain mutant
1na5	Integrin alpha m i domain
1oak	Crystal structure of the von willebrand factor (vwf) a1 domain in complex with the function blocking nmc-4 fab
1pt6	I domain from human integrin alpha1-beta1
1q0p	A domain of factor b
1qc5	I domain from integrin alpha1-beta1
1qcy	The crystal structure of the i-domain of human integrin alpha1beta1
1rd4	An allosteric inhibitor of lfa-1 bound to its i-domain
1rrk	Crystal structure analysis of the bb segment of factor b
1rs0	Crystal structure analysis of the bb segment of factor b complexed with di-isopropyl-phosphate (dip)
1rtk	Crystal structure analysis of the bb segment of factor b complexed with 4-guanidinobenzoic acid
1sht	Crystal structure of the von willebrand factor a domain of human capillary morphogenesis protein 2: an anthrax toxin receptor
1shu	Crystal structure of the von willebrand factor a domain of human capillary morphogenesis protein 2: an anthrax toxin receptor
1sq0	Crystal structure of the complex of the wild-type von willebrand factor a1 domain and glycoprotein ib alpha at 2.6 angstrom resolution
1t0p	Structural basis of icam recognition by integrin alpahlbeta2 revealed in the complex structure of binding domains of icam-3 and alphalbeta2 at 1.65 a
1t6b	Crystal structure of b. anthracis protective antigen complexed with human anthrax toxin receptor
1tye	Structural basis for allostery in integrins and binding of ligand-mimetic therapeutics to the platelet receptor for fibrinogen
1u0n	The ternary von willebrand factor a1-glycoprotein ibalpha- botrocetin complex
1u0o	The mouse von willebrand factor a1-botrocetin complex
1u8c	A novel adaptation of the integrin psi domain revealed from its crystal structure
1uex	Crystal structure of von willebrand factor a1 domain complexed with snake venom bitiscetin
1v7p	Structure of ems16-alpha2-i domain complex
1xdd	X-ray structure of lfa-1 i-domain in complex with lfa703 at 2.2a resolution
1xdg	X-ray structure of lfa-1 i-domain in complex with lfa878 at 2.1a resolution
1xuo	X-ray structure of lfa-1 i-domain bound to a 1,4-diazepane- 2,5-dione inhibitor at 1.8a resolution
1zon	Cd11a i-domain without bound cation
1zoo	Cd11a i-domain with bound magnesium ion
1zop	Cd11a i-domain with bound magnesium ion
2adf	Crystal structure and paratope determination of 82d6a3, an antithrombotic antibody directed against the von willebrand factor a3-domain
2b2x	Vla1 rdeltah i-domain complexed with a quadruple mutant of the aqc2 fab
2i6q	Complement component c2a
2i6s	Complement component c2a
2ica	Cd11a (lfa1) i-domain complexed with bms-587101 aka 5-[(5s, 9r)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4- dioxo-1,3,7-triazaspiro [4.4]non-7-yl]methyl]-3- thiophenecarboxylicacid
2iue	Pactolus i-domain: functional switching of the rossmann fold
2o7n	Cd11a (lfa1) i-domain complexed with 7a-[(4-cyanophenyl) methyl]-6-(3,5-dichlorophenyl)-5-oxo-2,3,5,7a-tetrahydro- 1h-pyrrolo[1,2-a]pyrrole-7-carbonitrile
2odp	Complement component c2a, the catalytic fragment of c3- and c5-convertase of human complement
2odq	Complement component c2a, the catalytic fragment of c3- and c5-convertase of human complement
2ok5	Human complement factor b
2qtv	Structure of sec23-sar1 complexed with the active fragment of sec31
2vc2	Re-refinement of integrin alphaiibbeta3 headpiece bound to antagonist l-739758
2vdk	Re-refinement of integrin alphaiibbeta3 headpiece
2vdl	Re-refinement of integrin alphaiibbeta3 headpiece
2vdm	Re-refinement of integrin alphaiibbeta3 headpiece bound to antagonist tirofiban
2vdn	Re-refinement of integrin alphaiibbeta3 headpiece bound to antagonist eptifibatide
2vdo	Integrin alphaiibbeta3 headpiece bound to fibrinogen gamma chain peptide, hhlggakqagdv
2vdp	Integrin alphaiibbeta3 headpiece bound to fibrinogen gamma chain peptide,lggakqagdv
2vdq	Integrin alphaiibbeta3 headpiece bound to a chimeric fibrinogen gamma chain peptide, hhlggakqrgdv
2vdr	Integrin alphaiibbeta3 headpiece bound to a chimeric fibrinogen gamma chain peptide, lggakqrgdv
2win	C3 convertase (c3bbb) stabilized by scin
3bn3	Crystal structure of icam-5 in complex with al i domain
3bqm	Lfa-1 i domain bound to inhibitors
3bqn	Lfa-1 i domain bound to inhibitors
3e2m	Lfa-1 i domain bound to inhibitors
3eoa	Crystal structure the fab fragment of efalizumab in complex with lfa-1 i domain, form i
3eob	Crystal structure the fab fragment of efalizumab in complex with lfa-1 i domain, form ii
3f74	Crystal structure of wild type lfa1 i domain
3f78	Crystal structure of wild type lfa1 i domain complexed with isoflurane
3fcs	Structure of complete ectodomain of integrin aiibb3
3fcu	Structure of headpiece of integrin aiibb3 in open conformation
3gxb	Crystal structure of vwf a2 domain
3hi6	Crystal structure of intermediate affinity i domain of integrin lfa-1 with the fab fragment of its antibody al-57
3hrz	Cobra venom factor (cvf) in complex with human factor b
3hs0	Cobra venom factor (cvf) in complex with human factor b
3hxo	Crystal structure of von willebrand factor (vwf) a1 domain in complex with dna aptamer arc1172, an inhibitor of vwf- platelet binding
3hxq	Crystal structure of von willebrand factor (vwf) a1 domain in complex with dna aptamer arc1172, an inhibitor of vwf- platelet binding
3ibs	Crystal structure of conserved hypothetical protein batb from bacteroides thetaiotaomicron
3ije	Crystal structure of the complete integrin alhavbeta3 ectodomain plus an alpha/beta transmembrane fragment

Links (links to other resources describing this domain)

• PFAM: vwa
• INTERPRO: IPR002035