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Cell-Cell Interaction: Modulating Self Recognition Affinity

SBKB [doi:10.1038/sbkb.2012.129]
Featured Article - March 2013
Short description: Subtle changes that distinguish homophilic and heterophilic interactions in a cell surface molecule are revealed.

Electrostatic clash in homophilic interactions in nectin-2 (left) compared to modeled heterophilic interaction between nectins-2 and -3 (right). Figure courtesy of Steven Almo.

Cell-cell interactions are typically mediated by contacts between the extracellular (ecto) domains of membrane-spanning proteins. Nectin-1 to -4 form a class of cell adhesion molecules found in adherens and synaptic junctions. These transmembrane glycoproteins can undergo both homophilic and heterophilic interactions.

The nectin ectodomain contains a variable immunoglobulin (IgV) domain followed by two constant Ig (IgC) domains. To understand how the ectodomain can accommodate both homophilic and heterophilic contacts, Almo, Nathenson and colleagues (PSI NYSGRC HTP Center together with the Immune Function Network Parnership) have solved a 1.3Å-resolution structure of the human nectin-2 IgV domain (PDB 3R0N), which purified as a homodimer. The basic structure of nectin-2 IgV resembles other IgV domains: it has a two-layer β-sandwich topology and a conserved disulfide bond. The dimer architecture has a kinked appearance, also typical of other Ig superfamily members.

On the other hand, unlike many IgV domain interactions, the buried surface area is extensive (∼1,823 Å2). The interface contains a considerable number of hydrogen-bond contacts and van der Waals interactions. Single mutations disrupting either type of contact could impair homophilic association, as these mutant proteins were monomeric in solution.

Based on the nectin-2 homodimer structure and available data on nectins-1, -3 and -4, the authors explored the differences between homophilic and heterophilic interactions. Notably, in the center of the nectin-2 interface, the Glu141 residues from each monomer were involved in an unfavorable electrostatic clash. A charged residue was also seen in the human nectin-1 homophilic interaction (PDB 3ALP). Mutating this residue in the background of an Asn81 mutation that makes nectin-2 behave as a monomer restored homodimerization, pointing to the role of this clash in reducing the affinity of the homophilic interaction. In nectins-3 and -4, other charged residues occupy the equivalent position; not only does this eliminate the unfavorable electrostatics, but the changes actually introduce favorable polar interactions, providing an explanation for the higher affinity of heterophilic contacts as compared to homophilic contacts.

Another feature of cell-surface molecule interactions is the ability to form cis- and trans- interactions. Nectin-1 has been proposed to form cis-interactions via its N-terminal IgV domain, with the possibility for further trans-interactions mediated by head-to-head contacts between these cis-dimers. Based on their solution and structural analyses of nectin-2, however, the authors found no evidence to support the involvement of the IgV domains in cis-interactions, although they cannot exclude that cis-interactions might be a regulatory mechanism to limit trans-interactions.

Angela K. Eggleston

References

  1. D. Samanta et al. Structure of Nectin-2 reveals determinants of homophilic and heterophilic interactions that control cell-cell adhesion.
    Proc. Natl Acad. Sci. USA. 109, 14836-14840 (2012). doi:10.1073/pnas.1212912109

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Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health