Signal sequences hydrophobic region

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]. 

It has been suggested that the hydrophobic region may be involved in specific interactions, for example, with SRP (Emr et al., 1980 Silhavy et al., 1983). Clearly the mutations described above, as well as substitutions of j8-hydroxyleucine for leucine, could disrupt such interactions and cause an export defect. However, the wide variation of signal sequences, and their interchangeability, argue against its specific recognition on the basis of sequence. 

The cleavage site is defined primarily by the last three residues of the c region, von Heijne (1983) and Perlman and Halvorson (1983) have postulated the -3,-1 rule, which states that the residues that occupy positions -1 and — 3 of the signal sequence must have small neutral side chains. Alanine is most common by far at these sites, but cysteine, serine, threonine, and glycine are found occasionally. Position - 2 is more variable, but frequently has a large aromatic or hydrophobic side chain. The remaining residues of the c region are also variable, but are usually polar, and have been predicted to favor formation of a turn (Perlman and Halvorson, 1983) (see Section III,H). 

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