12 - substrates transmembrane sequences

The activity of 2,3-oxidosqualene cyclases is associated with microsomes, indicating their membrane-bound nature. However, the predicted amino acid sequences of these enzymes generally lack signal sequences and obvious transmembrane domains. Addition of hydrophobic membrane-localising regions to OSCs during evolution may have removed selection pressures that maintained alternate mechanisms for membrane localisation [33]. Consistent with this, there is a non-polar plateau on the surface of the A. acidocaldarius SC enzyme which is believed to be immersed in the centre of the membrane. The squalene substrate for SC is likely to diffuse from the membrane interior into the central cavity of the enzyme via this contact region [55,56]. 

The receptor-like protein tyrosine phosphatases have a transmembrane and, in some cases, a large extracellular domain with a very variable structme (Fig. 8.16). Many, but not all, membrane protein tyrosine phosphatases have two catalytic domains in the cytoplasmic region. The complete structme is very similar to the structure of transmembrane receptors. Understanding of their function is far from complete. Both the natural ligands and the substrate proteins following in the sequence are incompletely characterized. Several studies have demonstrated a role for receptor-like PTPs in neuronal cell adhesion signaling pathways. In cells of the neural tissue, a surface protein, contactin has been identified as ligand for the extracellular domain of a protein tyrosine phosphatase (Peles et al., 1995). 

The first evidence for the existence of the methylation of a prenylated peptidyl substrate was found in two jelly fungi, Tremella mesenterica and Tremella brasiliensis [30,31]. These peptide sequences are similar to the a-mating factor found in Saccharomyces cerevisiae, which is also prenylated at the C-terminus and contains an a-carboxyl methyl ester [32]. The gene product of the STEM in S. cerevisiae was found to be responsible for the methylation event for the a-factor-mating pheromone and the enzymatic activity of this methyltransferase was found only in the cellular membrane fractions [33,34]. Further analyses of Stel4p via epitope tagging determined that the enzyme is localized to the ER membrane and possesses six transmembrane segments, with majority of the enzyme exposed to the cytosol [35,36]. 

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