Adapter proteins

Ravichandran KS (2001) Signaling via She family adapter proteins. Oncogene 20 6322-6330... 

Toll/IL-l receptor domain - A domain found on the internal C-terminus of Toll-like receptors involved in binding the adapter proteins to initiate signalling inside the cell. 

Once the TLRs have bound their respective ligand they initiate a signalling cascade to alert the host to the presence of a threat. This signal begins with specific adapter proteins and leads to the activation of transcription factors such as NFkB, ERF-3 and IRF-7 as shown in Fig. 1. These activated transcription factors cause changes in gene expression typically leading to the production of cytokines. 

MyD88 was the first adapter protein to be discovered. As well as the TER. domain it contains a death domain (DD). MyD88 is used by all TLRs to signal with the exception of TLR-3, which requires TRIF. Its signalling pathway is outlined in Fig. 2. 

Kinoshita, A., Whelan, C. M., Smith, C. J., Mikhailenko, I., Rebeck, G. W., Strickland, D. K. and Hyman, B. T. (2001). Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein Role of the intracellular adapter protein Fe65. J. Neurosci. 21, 8354-61. 

GM-CSF and IL-3 have been shown to compete for receptors in some types of cells (e.g. eosinophils and KG-1 cells), indicating some structural homology between GM-CSF and IL-3 receptors, perhaps because they share certain subunits or adapter proteins. GM-CSF occupancy results in phosphorylation of certain proteins, and because the receptor possesses no inherent kinase activity, receptor occupancy must be linked to kinase activity via the generation of second messenger molecules. Pretreatment of cells with pertussis toxin abolishes the effects of GM-CSF, indicating the involvement of G-proteins in signal transduction. Priming of neutrophil functions with GM-CSF involves the activation of phospholipases A2 and D. 

McDonald, J., and Kreitman, M. (1991). Adaptive protein evolution at adh locus in Drosophila. Nature 351, 652-654. 

Arch, R. H., R. W. Gedrich, and C. B. Thompson, Tumor necrosis factor receptor-associated factors (TRAFs) — a family of adapter proteins that regulates life and death. Genes Dev, 1998, 12(18), 2821-30. 

Other cullins may have an adapter/protein binding site at their NTD tip... 

Zeth, K., Ravelli, R. B., Paal, K., Cusack, S., Bukau, B., and Dougan, D. A. Structural analysis of the adapter protein ClpS in complex with the N-terminal domain of ClpA. Nat. Struct. Biol. 2002, 9, 906-911. 

In addition, there are a number of borderline cases, whose sequence relationship to ubiquitin is hard to establish but most probably is real, as these proteins perform a similar function. One well-known example is the UBX domain [44, 45], which seems to replace an internal ubiquitin domain in a certain class of adapter proteins (see Section 12.5.2). Other examples are the autophagy proteins Apg8 and Apgl2 [23, 24] which act as ubiquitin-like modifiers. 

Figure 4.7 Interleukin 2 (IL-2) molecule. (Source Protein Date Bank, PDB ID 1M47. http //www.rcsb.org/pdb/cgi/explore.cgi job=summary pdbId=lM47 page=. Arkin MM, Randal M, Delano WL, et al. Binding of small molecules to an adaptive protein-protein interface, Proceedings of the National Academy of Sciences USA 100 1603 (2003). Used with permission.)...

S., Lanier, L.L., Lowell, G.A., and Nakamura, M.G. (2004) The limnunomodulatory Adapter Proteins DAP 12 and Fc Receptor y Ghain (FcRy) Regulate Development of Functional Osteoclasts through the Syk Tyrosine Kinase. Proceedings of the National Academy of Sciences of the USA 101, 6158-6163. 

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