Domain recruitment

TLR-2. Evidence for the bridging role of Mai comes from the presence of a phosphatidylinositol 4,5-bisphosphate (PEP2) binding domain at its N-terminus. This domain recruits Mai to areas of the plasma membrane rich in PEP2 and these areas have been shown to contain TLR-4. 

Qiacko et al, 1996). Cell growth is arrested when the type II Fey receptor bl (FcyRIIbl) associates with the B ceU receptor (BCR) by the interaction of their extracellular domains with immune complexes. Clustering FcyRIIbl with BCR induces the phosphorylation of the immimoreceptor tyrosine-based inhibitory motif (ITIM) within the FcyRIIb intracellular tail, which then allows SHIP to bind through its SH2 domain. Recruitment of SHIP to the cell membrane by FcyRIIb p-ITIM is believed to block extracellular uptake and cell growth via the inositol 5-phosphatase activity of SHIP. 

The following sections explore nature s use of domain swapping to evolve new function. These include the formation of multifunctional proteins, tandem duplication, domain recruitment, and cicular permutation (Fig. 1). The evolution of several enzymes in the purine (Fig. 2) and pyrimidine (Fig. 3) de novo biosynthetic pathways, as well as other enzymes, are discussed as illustrative examples. 

Fig. 1. Schematics of evolutionary mechanisms of domain swapping in nature. Multifunctional proteins arise from the fusion of the genes coding for individual enzymes. Often the individual domains of multifunctional proteins catalyze successive steps in metabolic pathways. In tandem duplication, a gene is duplicated and the 3 end of one copy is fused in-frame to the 5 end of the second copy. In domain recruitment, a functional unit (whole gene or gene fragment) from one gene is either inserted within or fused to an end of a second gene. Circular permuted genes are believed to arise via tandem duplication followed by introduction of new start and stop codons (Ponting el at, 1995).

The generation of functional versatility in proteins by reorganization of individual protein subunits or domains is summarized under the term domain recruitment . The idea behind domain recruitment has been vividly depicted by Ostermeier and Benkovic s adaptation of the cliche a thousand monkeys typing at a thousand typewriters would eventually reproduce the works of Shakespeare [40]. In reference to domain recruitment, these authors suggest that the writing would obviously work... 

Evidence for domain recruitment has been identified in a wide variety of proteins [47], mechanistically ranging from simple N- or C-terminal fusion to multiple internal insertions and possibly circular permutations [48]. A recent analysis of proteins in the protein structure database (PDB) has further indicated that structural rearrangements as a result of domain shuffling have significantly contributed to today s functional diversity [49]. A brief overview of the various modes of domain recruitment and their effects on function, is presented on examples of /lex-barrel structures. 

A variation thereof is the generation of bispecific antibodies [38]. In certain applications, these are designed to bind to a cancer-specific surface molecule with one binding domain, while the other binding domain recruits cytotoxic T cells to the pathogenic cell, inducing T-cell-dependent cytotoxicity [39]. 

Death domain receptors. The cytokine TNF (tumor necrosis factor) uses a type of receptor called the death domain receptor (Fig. 11.21). These receptors function as a trimer when they bind TNF (which is also a trimer). On TNF binding, an inhibitory protein called the silencer of death is released from the receptor. The receptor then binds and activates several adaptor proteins. One adaptor protein, FADD (fas-associated death domain), recruits and activates the zymogen form of a proteolytic enzyme called caspase. Caspases... 

Paulson M, Pisharody S, Pan L, Guadagno S, Mui AL, Levy DE Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J Biol Chem 1999 274 25343-25349. 

Lu, L., and Hong, W. (2003). Interaction of Arll-GTP with GRIP domains recruits autoantigens golgin-97 and golgin-245/p230 onto the Golgi. Mol. Biol. Cell 14, 3767-3781. 

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