Amino acid degradation ubiquitination

At least three distinct forms of the IP3-R have been identified, and these share an overall amino acid homology of 60-80%. Type I predominates in the cerebellum and has been most extensively studied. It is the largest of the 3 forms of the receptor and, unlike type II and III receptors, the gene possesses a 120 nucleotide insert. Type II IP3-Rs are found mainly in non-neural tissues, whereas type III receptors occur in both neural and non-neural tissues. In response to chronic activation, IP3-Rs are degraded via the ubiquitin-proteasome pathway [14] (see also Ch. 2). 

Although the ubiquitination site(s) of -catenin was previously unknown, two lysines of I/cBa located ten and nine residues upstream of the destruction motif had been shown to be necessary and sufficient for ubiquitination and degradation [18, 19]. By analogy, a jS-catenin lysine (Lysl9) 13 residues upstream of the destruction motif was predicted to be the site where / -catenin is ubiquitinated. This was confirmed by the in vitro ubiquitination assay, in which a 26-amino acid j8-catenin peptide that contains Lysl9 and the doubly phosphorylated destruction motif was ubiquitinated in an -dependent manner to an overall level comparable to an... 

It has been reported that the GRR that spans amino acid residues 476-304 in human pl05, is an important structural motif required for the generation of the p50 subunit of NF-kB (10). However, the mechanisms involved in this unique reaction have remained enigmatic. Since degradation of a protein via the ubiquitin pathway involves two steps, conjugation of ubiquitin and proteasomal degradation of the tagged substrate, it was important first to identify the step affected by the GRR. 

Substrate proteins are selected for Ub hgation based on a C-terminal target sequence. These sequences which, due to the occurrence of common amino acids, are known as PEST sequences, are targets for phosphorylation. In the phosphorylated form, they are recognized by the ubiquitin hgase complex and marked for degradation. 

First, as we have already noted, proteins with different functions always have different amino acid sequences. Second, thousands of human genetic diseases have been traced to the production of defective proteins. Perhaps one-third of these proteins are defective because of a single change in their amino acid sequence hence, if the primary structure is altered, the function of the protein may also be changed. Finally, on comparing functionally similar proteins from different species, we find that these proteins often have similar amino acid sequences. An extreme case is ubiquitin, a 76-residue protein involved in regulating the degradation of other proteins. The amino acid sequence of ubiquitin is identical in species as disparate as fruit flies and humans. 

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