Protein subfamilies

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

So far four G protein subfamilies have been identified and classified according to the more than 20 known a subunits (Gq/11, Gi/0, Gs, and G12/13) [6]. There is a similar variety of beta and gamma subunits. G proteins can act either stimulatory or inhibitory. 

Eisen JA, Sweder KS, Hanawalt PC (1995) Evolution of the SNF2 family of proteins subfamilies with distinct sequences and functions. Nucleic Acids Res 23 2715-2723 Falbo KB, Shen X (2006) Chromatin remodeling in DNA replication. J Cell Biochem 97 684-689 Fazzio TG, Gelbart ME, Tsukiyama T (2005) Two distinct mechanisms of chromatin interaction by the Isw2 chromatin remodeling complex in vivo. Mol Cell Biol 25 9165-9174... 

Wang, J., Ducret, A., Tu, Y., Kozasa, T., Aebersold, R., and Ross, E. M. (1998). RGSZ1, a Gz-selective RGS protein in brain. Structure, membrane association, regulation by Galphaz phosphorylation, and relationship to a Gz GTPase-activating protein subfamily./. Biol. Chem. 273, 26014-26025. 

Vogt R. G., Prestwich G. D. and Lemer M. R. (1991a) Odorant-binding-protein subfamilies associate with distinct classes of olfactory receptor neurons in insects. J. Neurobiol. 22, 74-84. 

Implicated in induction and differentiation of cartilaginous tissues during development are a number of growth factors and cytokines, including the TGF-P superfamily. Those implicated include bone morphogenetic protein subfamilies, fibroblast growth factor family, insulinlike growth factor family,... 

Since a-gustducin belongs to the Gai protein subfamily of Ga proteins, its activation should lead to a reduction of cyclic nucleotide levels via the stimulation of phosphodiesterases. Indeed, two phosphodiesterases were identified in gustatory tissue (McLaughlin et al. 1994) and a rapid decrease in cyclic AMP after stimulation... 

Figure 6.1 Predicted topology and domain organization of fungal ABC protein subfamilies. The figure depicts the predicted membrane topology and domain organization of all subfamilies encoding yeast ABC proteins (see text for details). NBD, nucleotidebinding domain NTE, N-terminal extension TMS, transmembrane segment.

Even if conserved residues can be part of interaction surfaces, other residues conserved in subfamilies, the so-called tree-determinants, can also be important for tracing functional interfaces. These tree-determinants point to positively selected changes in a protein family that potentially indicate the presence of functional-specific sites. In this position it is possible to find protein-protein interaction related sites [94,98]. The ability of these methods to predict sites that are specific [99] and the state-of-the-art in current methods for predicting functional sites [100] has been described in recent publications, including experiments demonstrating the capacity of those methods to predict residues that once swapped can produce a exchange of functional specificity between two protein subfamilies [65,101,102]. 

Kuwano M, Toh S, Uchiumi T, Takano H, Kohno K, Wada M. Multidrug resistance-associated protein subfamily transporters and drug resistance. Anticancer Drug Des 1999 14 123-131. 

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