Single-spanning transmembrane domains in cell growth and cell-cell interactions: More than meets the eye?

Abstract

As a whole, integral membrane proteins represent about one third of sequenced genomes, and more than 50% of currently available drugs target membrane proteins, often cell surface receptors. Some membrane protein classes, with a defined number of transmembrane (TM) helices, are receiving much attention because of their great functional and pharmacological importance, such as G protein-coupled receptors possessing 7 TM segments. Although they represent roughly half of all membrane proteins, bitopic proteins (with only 1 TM helix) have so far been less well characterized. Though they include many essential families of receptors, such as adhesion molecules and receptor tyrosine kinases, many of which are excellent targets for biopharmaceuticals (peptides, antibodies, et al.). A growing body of evidence suggests a major role for interactions between TM domains of these receptors in signaling, through homo and heteromeric associations, conformational changes, assembly of signaling platforms, etc. Significantly, mutations within single domains are frequent in human disease, such as cancer or developmental disorders. This review attempts to give an overview of current knowledge about these interactions, from structural data to therapeutic perspectives, focusing on bitopic proteins involved in cell signaling.

Figure 1

A pie chart representation of the distribution of single-spanning TM proteins in E. coli and humans according to their function. Data were replotted from Daley et al. and Almen et al.,

Figure 2

Examples of complexes between cell adhesion molecules and receptors tyrosine kinases. Reprinted from Orian-Rousseau V, Ponta H. Adhesion proteins meet receptors: a common theme? Adv Cancer Res. 2008; 101:63–92. Copyright 2008. Printed with permission from Elsevier.

Figure 3

Views of TM helix dimer structures from NMR. For each dimer, two views are presented, one showing the crossing angle and the second, rotated by 90 degrees around the (pseudo)-symmetry axis, showing the structure of the interface. Structures are: (A) Glycophorin A (1afo); (B) ξ-ξ dimer of T cell receptor (2 hac); (C) Receptor tyrosine kinase EphA1 (2k1k); (D) Integrin alphaIIb-beta3 TM complex (2k9j); (E) Receptor tyrosine kinase EphA2 (2k9y); (F) BNip3 TM domain dimer (in mitochondrial outer membrane) (2ka1); (G) TM domain of growth factor receptor ErbB2 (2jwa). Properties fo the structures are summarized in Table 1. Residues belonging to dimerization motifs or participating in dimer contacts are outlined in space-filling or stick representation and colored by amino acid type: Gly (yellow), Ala (brown), Val (tan), Leu (pink), Ile (green), Glu/Asp (purple), Ser (orange), Thr (mauve), Pro (gray), Tyr (blue-gray), Cys (lime). Molecular graphics rendered with VMD.

Figure 4

Another view of TM helix dimer structures. Projection of helical surfaces of each helix in a dimer were made with Ptuba and colored according to an inter-helix distance scheme, with deep red being the closest (3 Å) and deep blue the farthest (6 Å). A single helix projection is shown for homodimers (upper row), with the corresponding sequence in the lower row. Structures are: (A) Glycophorin A (1afo); (B) TM domain of growth factor receptor ErbB2 (2jwa); (C) ξ-ξ dimer of T-cell receptor (2 hac). Molecular graphics rendered with VMD.