Abstract
The structure of the testicular peptide hormone insulin-like factor 3 (INSL3) has been the subject of discussion for more than a decade. Some studies support that the central C-domain of INSL3 is proteolytically removed and that INSL3 is secreted by the testicular Leydig cells into circulation as a small heterodimer consisting of an A- and a B-chain linked by two disulfide bridges. Other studies support that the INSL3 peptide remains uncleaved and that the predominant structure of circulating INSL3 is the larger pro-form. Furthermore, the structure of INSL3 could differ between species, and both structural forms of INSL3 could, in principle, be present in circulation. Recently, we have developed a mass spectrometry (MS)-based method for INSL3 in human serum that provides new information about the structure of circulating INSL3. Based on recent and newly presented data, we argue that in healthy men, the common, and probably the only, form of circulating INSL3 is the smaller AB heterodimer. For the first time, we demonstrate that the same analytical principle, with slight modifications, can also be applied to sera from other species, and we show that the INSL3 AB heterodimer is also present in serum from rodents. Improved understanding of the structure and biochemistry of circulating INSL3 could be valuable for the interpretation of INSL3 as a marker for reproductive and developmental disorders in humans and domesticated animals.
Highlights
The peptide hormone insulin-like factor 3 (INSL3) is a member of the insulin/insulin-like growth factor/relaxin superfamily that in humans include insulin, insulin-like growth factor (IGF)-I and IGF-II, relaxin (RLN) 1-3, and INSL3-6 [1]
The peptide hormone INSL3 is being explored as a diagnostic marker for developmental and reproductive disorders in both humans and domesticated animals
A detailed understanding of the peptide structure and biochemistry could be valuable for the reliable measurement and interpretation of circulating INSL3 levels
Summary
The peptide hormone insulin-like factor 3 (INSL3) is a member of the insulin/insulin-like growth factor/relaxin superfamily that in humans include insulin, insulin-like growth factor (IGF)-I and IGF-II, relaxin (RLN) 1-3, and INSL3-6 [1]. The postnatal function of INSL3 is poorly understood, but it may play a role in the regulation of male germ cell survival [5], bone metabolism [6], and muscle growth [7]. Members of the insulin peptide family are processed according to the classical mechanism for peptide hormones [10], whereby the N-terminal signal peptide is proteolytically cleaved from the nascent polypeptide chain during translation on ribosomes (Figure 1). The central C-domain is not excised from the family members IGF-I and IGF-II, and both these peptides present in circulation as single chains of amino acids. Whether the central C-domain is cleaved from human INSL3, like the family member insulin, or whether the intact form of pro-INSL3 is released into circulation, like the family members IGF-I and IGF-II, is still being debated [11]
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