The insulin receptor and signal transduction

The cytoplasmic domain of the P-subunit displays three distinct sub-domains (a) the juxtam-embrane domain , implicated in recognition/binding of intracellular substrate molecules (b) the tyrosine kinase domain, which (upon receptor activation) displays tyrosine kinase activity (c) the C-terminal domain, whose exact function is less clear, although site-directed mutagenesis studies implicate it promoting insulin s mitogenic effects. 

Insulin preparations used initially were little more than crude pancreatic extracts. The therapeutic value of such products was marginal, as severe adverse reactions were commonplace (due to the presence of impurities). This was made worse by the frequency of injections required. The introduction of an acid-alcohol precipitation step yielded insulin preparations of moderate purity, thus partially overcoming the range and severity of side effects noted. 

Although insulin was first crystallized in 1926, the factors promoting crystal growth were poorly understood and yielded inconsistent results. It was almost 10 years later when researchers discovered that the addition of zinc to a crude extract promoted reproducible crystallization (zinc addition yields a characteristic rhombohedral crystal, the basic crystal unit being the insulin hexamer, stabilized by the two zinc atoms). 

Protein class Gene product Insulin effect (f or in transcription rate) 

By the mid-1930s, commercial insulin was being prepared by crystallization from crude porcine or bovine extracts. The crystallized preparation was generally subjected to a recrystallization step in order to further increase the product s purity. Such preparations are termed conventional insulins (Box 8.2). 

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