Over the last decade, the concept of an IGFBP family has been well accepted, based on structural similarities and on functional abilities to bind IGFs with high affinities. The existence of other potential IGFBPs was left open. The discovery of proteins with N-terminal domains bearing striking structural similarities to the N terminus of the IGFBPs, and with reduced, but demonstrable, affinity for IGFs, raised the question of whether these proteins were "new" IGFBPs (22, 23, 217). The N-terminal domain had been uniquely associated with the IGFBPs and has long been considered to be critical for IGF binding. No other function has been confirmed for this domain to date. Thus, the presence of this important IGFBP domain in the N terminus of other proteins must be considered significant. Although these other proteins appear capable of binding IGF, their relatively low affinity and the fact that their major biological actions are likely to not directly involve the IGF peptides suggest that they probably should not be classified within the IGFBP family as provisionally proposed (22, 23). The conservation of this single domain, so critical to high-affinity binding of IGF by the six IGFBPs, in all of the IGFBP-rPs, as well, speaks to its biological importance. Historically, and perhaps, functionally, this has led to the designation of an "IGFBP superfamily". The classification and nomenclature for the IGFBP superfamily, are, of course, arbitrary; what is ultimately relevant is the underlying biology, much of which still remains to be deciphered. The nomenclature for the IGFBP related proteins was derived from a consensus of researchers working in the IGFBP field (52). Obviously, a more general consensus on nomenclature, involving all groups working on each IGFBP-rP, has yet to be reached. Further understanding of the biological functions of each protein should help resolve the nomenclature dilemma. For the present, redesignating these proteins IGFBP-rPs simplifies the multiple names already associated with each IGFBP related protein, and reinforces the concept of a relationship with the IGFBPs. Beyond the N-terminal domain, there is a lack of structural similarity between the IGFBP-rPs and IGFBPs. The C-terminal domains do share similarities to other internal domains found in numerous other proteins. For example, the similarity of the IGFBP C terminus to the thyroglobulin type-I domain shows that the IGFBPs are also structurally related to numerous other proteins carrying the same domain (87). Interestingly, the functions of the different C-terminal domains in members of the IGFBP superfamily include interactions with the cell surface or ECM, suggesting that, even if they share little sequence similarities, the C-terminal domains may be functionally related. The evolutionary conservation of the N-terminal domain and functional studies support the notion that IGFBPs and IGFBP-rPs together form an IGFBP superfamily. A superfamily delineates between closely related (classified as a family) and distantly related proteins. The IGFBP superfamily is therefore composed of distantly related families. The modular nature of the constituents of the IGFBP superfamily, particularly their preservation of an highly conserved N-terminal domain, seems best explained by the process of exon shuffling of an ancestral gene encoding this domain. Over the course of evolution, some members evolved into high-affinity IGF binders and others into low-affinity IGF binders, thereby conferring on the IGFBP superfamily the ability to influence cell growth by both IGF-dependent and IGF-independent means (Fig. 10). A final word, from Stephen Jay Gould (218): "But classifications are not passive ordering devices in a world objectively divided into obvious categories. Taxonomies are human decisions imposed upon nature--theories about the causes of nature's order. The chronicle of historical changes in classification provides our finest insight into conceptual revolutions

/pdf/the-insulin-like-growth-factor-binding-protein-igfbp-41vwms7yip.pdf

The insulin-like growth factor-binding protein (IGFBP) superfamily.

Publisher Summary This chapter discusses the insulin-like growth factor (IGF) binding proteins—namely, IGF-I and IGF-II The IGFs are purified from human plasma and cell culture medium by virtue of their ability to stimulate the growth of cartilage or cultured fibroblasts, or their insulin-like activity The IGFs are synthesized in many fetal and postnatal tissues and are capable of acting locally IGF-I and IGF-II are single-chain 75-kDa polypeptides that are chemically related to insulin They bind with high affinity to IGF-I receptors that are thought to mediate most of their biological actions The IGF-I receptor is a homolog of the insulin receptor, having a heterotetrameric structure and a tyrosine kinase domain in the cytoplasmic portion of the β-subunit that phosphorylates the receptor and other substrates, and presumably is involved in transmembrane signaling Hybrid receptors consisting of one αβ IGF-I receptor heterodimer and one αβ insulin receptor heterodimer are described IGF-II also binds with high affinity to the IGF-II/Mannose 6-phosphate receptor IGF-II added with the IGF-II/Mannose 6-phosphate receptor stimulated the activation of the guanosine triphosphate (GTP) binding protein G i-2  The IGFs participate in the physiological growth of the developing child, fetus, and embryo

Insulin-like growth factor binding proteins.

Western ligand blot analysis of the different molecular forms of insulin-like growth factor-binding protein IGF-BP) in serum and plasma samples from 89 pregnant women has revealed a marked decrease, after the second month of pregnancy, in the 41.5 and 38.5K species (which are the binding units of the 150K complex) as well as in the 24K form. There was also a slight decrease in the 34K form, the 30K form was unaffected, and additional 21.5 and 20K bands appeared. Cross-linking experiments demonstrated the disapperance of a 49K band which is characteristic of the 150K complex. The alterations of the electrophoretic profile of the BPs were accompanied by a decrease in binding activity of up to 90%. Gel filtration at pH 7.4 confirmed that the decrease was essentially attributable to changes in the 150K complex BPs: 1) material eluting in the 150K zone contained only one third of the binding activity, as opposed to three quarters in reference material; 2) radiocompetition experiments illustrated the loss of affinity for IGF-I and IGF-II of the BPs extracted from the 150K complex; 3) ligand blot analysis revealed, in contrast with the virtual disappearance of the 41.5 and 38.5K forms, the appearance of a broad indistinct band at 30K and additional bands at 21.5 and 20K. With immunoblotting, the anti-IGF-BP-3 antibody, which specifically recognizes the 41.5 and 38.5K species, cross-reacted with this 30K material. The alterations of the BPs appeared to be enzymatic. When pregnancy serum was mixed with reference serum, the 41.5, 38.5, and 24K forms contributed by the reference serum were markedly reduced after 30 min of incubation at 37 C. However, these alterations could be prevented by incubation at either 0 or at 37 C in the presence of EDTA or aprotinin and could be curbed in the presence of high concentrations of phenylmethylsulfonylfluoride. Unmixed reference serum incubated at 37 C yielded an unchanged BP profile. Incubation of pregnancy serum with hypopituitary serum, which has elevated levels of the 34 and 30K BPs, resulted in a marked decrease in the 41.5 and 38.5K forms, a slight alteration of the 34K form, and no change in the 30K form. These findings suggest that during pregnancy, enzymatic (probably protease) activity either appears or is significantly increased in the circulation, which specifically degrades some of the IGF-BPs.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence of Enzymatic Degradation of Insulin-Like Growth Factor-Binding Proteins in the 150K Complex during Pregnancy*

Recent years have witnessed growing interest in the role of peptides in animal nutrition. Chemical, enzymatic, or microbial hydrolysis of proteins in animal by-products or plant-source feedstuffs before feeding is an attractive means of generating high-quality small or large peptides that have both nutritional and physiological or regulatory functions in livestock, poultry and fish. These peptides may also be formed from ingested proteins in the gastrointestinal tract, but the types of resultant peptides can vary greatly with the physiological conditions of the animals and the composition of the diets. In the small intestine, large peptides are hydrolyzed to small peptides, which are absorbed into enterocytes faster than free amino acids (AAs) to provide a more balanced pattern of AAs in the blood circulation. Some peptides of plant or animal sources also have antimicrobial, antioxidant, antihypertensive, and immunomodulatory activities. Those peptides which confer biological functions beyond their nutritional value are called bioactive peptides. They are usually 2–20 AA residues in length but may consist of >20 AA residues. Inclusion of some (e.g. 2–8%) animal-protein hydrolysates (e.g., porcine intestine, porcine mucosa, salmon viscera, or poultry tissue hydrolysates) or soybean protein hydrolysates in practical corn- and soybean meal-based diets can ensure desirable rates of growth performance and feed efficiency in weanling pigs, young calves, post-hatching poultry, and fish. Thus, protein hydrolysates hold promise in optimizing the nutrition of domestic and companion animals, as well as their health (particularly gut health) and well-being.

/pdf/protein-hydrolysates-in-animal-nutrition-industrial-53vyg9vewn.pdf

Protein hydrolysates in animal nutrition: Industrial production, bioactive peptides, and functional significance.

Insulin-like growth factor-I (IGF-I) and IGF-II are associated in the blood with specific binding proteins (BPs), forming complexes that elute in gel filtration with estimated mol wt around 40 and 150 kD. The latter appears to be under GH control. Five molecular forms of BP (41.5, 38.5, 34, 30, and 24 kD) have been identified by Western blotting using 125I-labeled IGF. All five forms are present in the smaller complexes, but only the 41.5- and 38.5-kD forms are found in the larger complexes. In this study immunoblotting showed that the 41.5- and 38.5-kD forms were recognized by antibodies directed against the GH-dependent BP purified from human plasma, and the 30-kD form was recognized by antibodies directed against the BP purified from amniotic fluid. The 34- and 24-kD forms proved to be immunologically unrelated to the other three. In sera with large quantities of the 41.5- and 38.5-kD forms, an additional band was often observed immediately ahead of the migration front of the 30 kD band. This was recognized by the anti-GH-dependent BP antibody and probably corresponds to a degradation product of the 41.5- and 38.5-kD BPs. Serum 41.5- and 38.5-kD BPs have been found to be elevated in acromegaly, where GH hypersecretion causes increased IGF-I levels, and diminished in cases of genetic or idiopathic GH deficiency and defects of the GH receptor (Laron's syndrome), where both IGF-I and IGF-II are decreased, as well as in Pygmy adults and children who have isolated IGF-I deficiency. In all of these conditions, the proportions of the 34- and 30-kD forms were inversely related to those of the 41.5- and 38.5-forms. Under treatment, the BP profiles tended to return to normal. In cases of GH deficiency caused by a tumor, the BP profiles resembled those of hypopituitary or normal serum, depending on whether IGF levels were diminished or normal. It, therefore, seems that BP synthesis is coordinated with IGF-I synthesis and may not be directly GH dependent. The results of neutral pH gel filtration analysis of hypopituitary (idiopathic and tumoral) and normal sera point to a relationship between the levels of circulating IGFs and those of the 150-kD IGF-BP complex whose binding units are the 41.5- and 38.5-kD BPs. It, therefore, seems that the 150-kD complex controls the bioavailability of IGF-I and IGF-II.(ABSTRACT TRUNCATED AT 400 WORDS)

Molecular forms of serum insulin-like growth factor (IGF)-binding proteins in man: relationships with growth hormone and IGFs and physiological significance.

Two different insulin-like growth-factor (IGF)-binding proteins have been found in human blood, one of high molecular mass and dependent on growth hormone for synthesis, the other of low molecular mass and independent of growth hormone The small IGF-binding protein is abundant in human amniotic fluid Its amino acid sequence has now been determined by direct analysis of the protein and its proteolytic fragments Also, by immunoscreening a partial cDNA clone was isolated from a human hepatoma cell line The mature protein consists of 234 amino acids and is coded for by an mRNA of approximately 1700 nucleotides in length The primary structure of the protein reveals 18 Cys residues in N-terminal and C-terminal clusters and an Arg-Gly-Asp peptide sequence, common to extracellular proteins binding to receptors of the integrin family A protein-sequence polymorphism was detected at position Ile/Met-228, indicating possible allelic variation The 3'-untranslated mRNA sequence has a high A + T content and shows five copies of an ATTTA sequence, which has been shown to be involved in the regulation of the stability of certain mRNAs coding for growth-regulating proteins

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1989.tb14641.x

Human insulin-like growth-factor-binding protein. Low-molecular-mass form: protein sequence and cDNA cloning.

We have isolated from pig intestine a 60-residue polypeptide initially identified by its inhibition of glucose-induced insulin secretion from perfused pancreas. The amino acid sequence of this porcine polypeptide was determined and found to be markedly similar to that of the pancreatic secretory trypsin inhibitor (41% residue identities). Furthermore, the disulfide arrangements of these two proteins appear identical, suggesting related overall conformations. However, the polypeptide, now named PEC-60 (peptide with N-terminal glutamic acid, C-terminal cysteine, and a total of 60 residues), was found not to inhibit trypsin. The amino acid sequence is also similar to that of a peptide recently isolated from rat bile/pancreatic juice which stimulates the release of cholecystokinin. The biological role of PEC-60 is not known, but the effect on insulin secretion and the homologies observed suggest important biological activities and interesting structural relationships.

https://www.pnas.org/content/pnas/86/21/8590.full.pdf

Isolation and characterization of a 60-residue intestinal peptide structurally related to the pancreatic secretory type of trypsin inhibitor: influence on insulin secretion.

The NH2-terminal region of rat liver glucose-6-phosphate dehydrogenase (EC 1.1.1.49) is shown to differ radically from a reported amino acid sequence for the fruit fly enzyme and from one for the human enzyme. The results indicate considerable differences in the translational start point. However, a close relationship with another reported sequence for the human enzyme is established, now showing agreement between an indirectly deduced and a directly analyzed NH2-terminal structure of this enzyme type. The results provide evidence of one structural motif common to mammalian species but also suggest that genetic inconstancy 5' to, or at the start of, the region coding for the enzyme protein could be a source of intra- and interspecies diversity. This is of interest in relation to the large number of genetic variants of human glucose-6-phosphate dehydrogenase.

Molecular diversity of glucose-6-phosphate dehydrogenase: rat enzyme structure identifies NH2-terminal segment, shows initiation from sites nonequivalent in different organisms, and establishes otherwise extensive sequence conservation

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Human insulin-like growth-factor-binding protein. Low-molecular-mass form: protein sequence and cDNA cloning.

Isolation and characterization of a 60-residue intestinal peptide structurally related to the pancreatic secretory type of trypsin inhibitor: influence on insulin secretion.

Molecular diversity of glucose-6-phosphate dehydrogenase: rat enzyme structure identifies NH2-terminal segment, shows initiation from sites nonequivalent in different organisms, and establishes otherwise extensive sequence conservation