The Human Insulin/Relaxin Superfamily: New Members and Functions

摘要

Some twenty years after Sanger's landmark report of the primary structure of bovine insulin, it was shown that porcine relaxin also consisted of two chains that were cross bridged by three disulfide bonds in an identical arrangement to that of insulin [1]. This established the concept of the insulin superfamily of peptides and led to a vigorous search for additional members in not only the human but other mammals as well. With the emergence of novel DNA sequencing methods, analysis of human DNA showed the presence of not one but two genes for relaxin which were named genes 1 and 2 [2]. Subsequent work has since shown that gene 1 relaxin is only found in humans and higher primates and has an unknown function. Shortly afterwards, gene 2 relaxin was identified and is now recognized to be the major circulating form of relaxin in all mammals and is simply called relaxin. The next two members of the superfamily to be identified were insulin-like growth factors 1 and II which, unlike all other members are single-disulflde chain peptides that possess the insulin-like crosslinks. Differential screening of testis-specific transcripts led to the identification of insulin-like peptide 3 (INSL3) and analysis of human placental cDNA library resulted in the discovery of the gene for insulin-like peptide 4 (INSL4). It has not yet been confirmed that INSL4 is expressed in vivo and, if so, whether it consists of a one or two-chain structure. EST databases were used to identify the presence of both insulin-like peptide 5 (INSL5) and insulin-like peptide 6 (INSL6). Finally, the availability of the Celera Genomic database in the early 2000s allowed the most unexpected discovery of the final member of the superfamily, relaxin-3 [2]. Membership thus numbers ten peptides. The primary structure varies considerably between these members; only seven residues are invariant with six of these being the cysteine residues that make up the three disulfide bonds (Figure 1).