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. 2001 Jan 15;20(1-2):12-8.
doi: 10.1093/emboj/20.1.12.

CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs

K Kitadokoro  1 , D Bordo, G Galli, R Petracca, F Falugi, S Abrignani, G Grandi, M Bolognesi
Affiliations

CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs

K Kitadokoro et al. EMBO J. .

Abstract

Human CD81, a known receptor for hepatitis C virus envelope E2 glycoprotein, is a transmembrane protein belonging to the tetraspanin family. The crystal structure of human CD81 large extracellular domain is reported here at 1.6 A resolution. Each subunit within the homodimeric protein displays a mushroom-like structure, composed of five alpha-helices arranged in 'stalk' and 'head' subdomains. Residues known to be involved in virus binding can be mapped onto the head subdomain, providing a basis for the design of antiviral drugs and vaccines. Sequence analysis of 160 tetraspanins indicates that key structural features and the new protein fold observed in the CD81 large extracellular domain are conserved within the family. On these bases, it is proposed that tetraspanins may assemble at the cell surface into homo- and/or hetero-dimers through a conserved hydrophobic interface located in the stalk subdomain, while interacting with other liganding proteins, including hepatitis C virus E2, through the head subdomain. The topology of such interactions provides a rationale for the assembly of the so-called tetraspan-web.

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Figures

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Fig. 1. Amino acid sequence alignment of tetraspanin LEL domains from mammalian sources. Letters indicating the secondary structure [as obtained from PROCHECK (Laskowski et al., 1993): H, α-helix; G, 310 helix] are shown on the top line. On the left, protein names and sources are indicated. The Entrez accession Nos for the sequences used in the alignment are: human CD81, NP_004347; tamarin (Saguinus oedipus), CAB89875; rat, NP_037219; mouse, P35762; human CD9, NP_001760; human TSPAN2, NP_005716; mouse CD53, NP_031677; human CD82, NP_002222; human CD63, NP_001771; human TALLA1, AAF4412; human NET4, AAC17120. Amino acid sequences of CD81 from chimpanzee, green monkey and hamster have been obtained from Pileri et al. (1998). The last four sequences contain insertions, which have not been included in the alignment to avoid the introduction of long gaps, located between pairs of lower case underlined residues. In detail, the insertion stretches are: in CD82, eLMNRPEVTy and sLSVRKGFCEAPGNRTQSGNHPEDWPv; in CD63, dWEKIPs, cINVTVGc and kAi; in TALLA1, sPYFLEh, cMNETDc and tVAATKVNq; and in NET4, aFGADDWNLNIYFNCt and dVINTQCGYDARQKPEVDQQIv. The conserved Cys residues are enclosed in yellow boxes. Amino acids involved in the association interface are shown in pink boxes. The residues that differ between hCD81-LEL and agmCD81-LEL or tamCD81-LEL are boxed in green and blue, respectively. Note that residue 163 is mutated in both agmCD81-LEL and tamCD81-LEL.
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Fig. 2. Stereoview of the dimeric hCD81-LEL. The view, generated with MOLSCRIPT and RASTER3D (Kraulis, 1991; Merritt and Murphy, 1994), shows the two subunits in blue and purple. The helix labels are distinguished in the two protomers by a prime. The molecular 2-fold axis is close to vertical (A) and located between the N- and C-termini of the two chains. Solid dots (in the purple subunit) trace an approximate path for residues 238–241 not observed in the electron density maps. In (B), the 2-fold axis is orthogonal to the drawing plane. (C) Stereoview of the hCD81-LEL isolated protomer. The view highlights the head subdomain localization relative to the N- and C-terminal helices (α-helices A and E, respectively), and the labeling of secondary structure elements. The two disulfide bridges are shown in yellow.
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Fig. 2. Stereoview of the dimeric hCD81-LEL. The view, generated with MOLSCRIPT and RASTER3D (Kraulis, 1991; Merritt and Murphy, 1994), shows the two subunits in blue and purple. The helix labels are distinguished in the two protomers by a prime. The molecular 2-fold axis is close to vertical (A) and located between the N- and C-termini of the two chains. Solid dots (in the purple subunit) trace an approximate path for residues 238–241 not observed in the electron density maps. In (B), the 2-fold axis is orthogonal to the drawing plane. (C) Stereoview of the hCD81-LEL isolated protomer. The view highlights the head subdomain localization relative to the N- and C-terminal helices (α-helices A and E, respectively), and the labeling of secondary structure elements. The two disulfide bridges are shown in yellow.
None
Fig. 2. Stereoview of the dimeric hCD81-LEL. The view, generated with MOLSCRIPT and RASTER3D (Kraulis, 1991; Merritt and Murphy, 1994), shows the two subunits in blue and purple. The helix labels are distinguished in the two protomers by a prime. The molecular 2-fold axis is close to vertical (A) and located between the N- and C-termini of the two chains. Solid dots (in the purple subunit) trace an approximate path for residues 238–241 not observed in the electron density maps. In (B), the 2-fold axis is orthogonal to the drawing plane. (C) Stereoview of the hCD81-LEL isolated protomer. The view highlights the head subdomain localization relative to the N- and C-terminal helices (α-helices A and E, respectively), and the labeling of secondary structure elements. The two disulfide bridges are shown in yellow.
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Fig. 3. Stereoview of part of the residues packing against the Tyr127 side chain at the core of the head subdomain, together with the Cys156–Cys190 disulfide. The Cys157–Cys175 disulfide has not been drawn for clarity. The electron density of the refined model (2Fo – Fc map) is represented at the 1σ level.
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Fig. 4. View of the molecular surface of hCD81-LEL. The dimer (GRASP view; Nicholls et al., 1991) is in an orientation rotated by ∼90° around the vertical axis relative to that of Figure 2A. Such an orientation brings α-helices C and D into the foreground; they are labeled in the exposed low-polarity region (white) of the molecular surface. The two amino acid residues shown to play a role in hCD81-LEL–HCV-E2 protein interaction are also indicated.
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References

    1. Abrahams J.P. and Leslie,A.G.W. (1996) Methods used in the structure determination of bovine mitochondrial F1 ATPase. Acta Crystallogr. D, 52, 30–42. - PubMed
    1. Berditchevski F., Zutter,M.M. and Hemler,M.E. (1996) Characterization of novel complexes on the cell surface between integrins and proteins with 4 transmembrane domains (TM4 proteins). Mol. Biol. Cell, 7, 193–207. - PMC - PubMed
    1. Berman H.M., Westbrook,J., Feng,Z., Gilliland,G., Bhat,T.N., Weissig,H., Shindyalov,I.N. and Bourne,P.E. (2000) The Protein Data Bank. Nucleic Acids Res., 28, 235–242. - PMC - PubMed
    1. Brünger A.T. et al. (1998) Crystallography & NMR system (CNS): a new software suite for macromolecular structure determination. Acta Crystallogr. D, 54, 905–921. - PubMed
    1. Cha J.H., Brooke,J.S., Ivey,K.N. and Eidels,L. (2000) Cell surface monkey CD9 antigen is a coreceptor that increases diphtheria toxin sensitivity and diphtheria toxin receptor affinity. J. Biol. Chem., 275, 6901–6907. - PubMed

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