Structures of IgSF cell surface receptors and related proteins

Figure 1A shows examples of IgSF cell surface receptor structures. The extracellular region of CDS includes a single V domain which dimerizes like the variable light and heavy chains of an antibody. The structure of a CD8/MHC class I complex shows that residues in Complementarity Determining Region (CDR)-like loops and j3-strands of the CD8 homo-dimer contact the a2~, a3-, and /32-microglobulin domains of MHC class I. The extracellular regions of CD4 and CD2 are stable as monomers and include four and two IgSF domains, respectively. In both structures, an N-terminal V-like domain is followed by a C2 domain. In CD4, a continuous 3 strand connects the first and second domain which form an extensive and rigid interface. This structure is very similar to the structure including the third and fourth domain of CD4. Structures of CD4 including all four extracellular domains in different crystal lattices reveals that domains 2 and 3 are more flexibly connected. In CD2, the two domains are connected by a linker and the interface is less extensive. Despite

Figure 1 Cell surface proteins of the IgSF and related molecules. Structures are represented as Ca traces. N- and C-termini are labeled. (A) Three IgSF members: CD8, CD4 and CD2. (B) Structure of a four-domain fragment of fibronectin. The three-dimensional structure of FN type III Is similar to IgSF C domains.

Figure 1 Cell surface proteins of the IgSF and related molecules. Structures are represented as Ca traces. N- and C-termini are labeled. (A) Three IgSF members: CD8, CD4 and CD2. (B) Structure of a four-domain fragment of fibronectin. The three-dimensional structure of FN type III Is similar to IgSF C domains.

these differences, the relative orientation of the two domains is similar in CD4 and CD2.

Structures of a V„ domain and (3 chain of different TCRs, a complete mouse TCR (and its preliminary complex with MHC class I), and a human TCR/ MHC class I complex have been reported. These structures confirm the structural similarity of antibodies and TCRs. In the V„ domain, which forms a tetramer of homodimers, the C" strand switches the sheet, a departure from V domain structure (see above). The (3 chain includes a V and a C domain which form an extensive interface (two to four times larger than in antibody structures). Overall, the mouse and human TCR structures are similar. In the mouse TCR structure, the Ca domain, which is disordered in the human TCR, substantially departs from known IgSF structure types. In the structure of the complex with peptide-bound MHC class I, the TCR binds with its CDR-like loops diagonally across the composite MHC/peptide surface. The orientation is such that the Va CDR loop 1 contacts the N-ter-minal and the V/3 CDR loop 3 the C-terminal region of the peptide.

In Figure IB, a structure consisting of four fib-ronectin (FN) type III domains is shown. FN type III domains are structurally similar to C2 domains, but are not included in the IgSF. Their structure is a sandwich of a four-stranded and a three-stranded p sheet. The domain lacks the Ig disulfide bond, and the packing of its hydrophobic core is distinct from the IgSF. FN type III domains are found in extracellular matrix proteins and in cytokine receptors. Domain 10 of fibronectin includes an RGD sequence in a loop and is therefore an integrin ligand and implicated in cell adhesion. Although the structures of single FN type III domains are very similar, their domain interfaces are not conserved. The two central domains display a relative orientation similar to CD4 and CD2.

Cadherins, also distantly related to the IgSF, are homophilic and calcium-dependent adhesion molecules. Like fibronectin, cadherins may include ten or more extracellular domains. The interfaces between domains are stabilized by calcium binding which also supports dimerization of cadherin domains. Crystal packing has suggested different ways in which cadherins interact. On the basis of crystal lattice interactions, models have been proposed for the formation of network-like multivalent cellular adhesion interfaces.

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