SMART: Pfam domain IGF2

The domain within your query sequence starts at position 123 and ends at position 177; the E-value for the IGF2_C domain shown below is 6.9e-30.

KFFQYDTWRQSAGRLRRGLPALLRARRGRMLAKELKEFREAKRHRPLIVLPPKDP

IGF2_C

PFAM accession number:	PF08365
Interpro abstract (IPR013576):	The insulin family of proteins groups together several evolutionarily related active peptides [ (PUBMED:6107857) ]: these include insulin [ (PUBMED:6243748) (PUBMED:503234) ], relaxin [ (PUBMED:10601981) (PUBMED:8735594) ], insect prothoracicotropic hormone (bombyxin) [ (PUBMED:8683595) ], insulin-like growth factors (IGF1 and IGF2) [ (PUBMED:2036417) (PUBMED:1319992) ], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [ (PUBMED:2036417) (PUBMED:1319992) (PUBMED:9141131) ]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain. Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver [ (PUBMED:6243748) ]. Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth [ (PUBMED:6243748) ]. Insulin is synthesised as a prepropeptide from which an endoplasmic reticulum-targeting sequence is cleaved to yield proinsulin. The sequence of prosinsulin contains 2 well-conserved regions (designated A and B), separated by an intervening connecting region (C), which is variable between species [ (PUBMED:503234) ]. The connecting region is cleaved, liberating the active protein, which contains the A and B chains, held together by 2 disulphide bonds [ (PUBMED:503234) ]. Insulin-like Growth Factor Binding Proteins (IGFBP) are a group of vertebrate secreted proteins, which bind to IGF-I and IGF-II with high affinity and modulate the biological actions of IGFs. The IGFBP family has six distinct subgroups, IGFBP-1 through 6, based on conservation of gene (intron-exon) organisation, structural similarity, and binding affinity for IGFs. Across species, IGFBP-5 exhibits the most sequence conservation, while IGFBP-6 exhibits the least sequence conservation. The IGFBPs contain inhibitor domain homologues, which are related to MEROPS protease inhibitor family I31 (equistatin, clan IX). All IGFBPs share a common domain architecture ( IPR000867 : IPR000716 ). While the N-terminal ( IPR000867 IGF binding protein domain), and the C-terminal ( IPR000716 thyroglobulin type-1 repeat) domains are conserved across vertebrate species, the mid-region is highly variable with respect to protease cleavage sites and phosphorylation and glycosylation sites. IGFBPs contain 16-18 conserved cysteines located in the N-terminal and the C-terminal regions, which form 8-9 disulphide bonds [ (PUBMED:11874691) ]. As demonstrated for human IGFBP-5, the N terminus is the primary binding site for IGF. This region, comprised of Val49, Tyr50, Pro62 and Lys68-Leu75, forms a hydrophobic patch on the surface of the protein [ (PUBMED:9822601) ]. The C terminus is also required for high affinity IGF binding, as well as for binding to the extracellular matrix [ (PUBMED:9725901) ] and for nuclear translocation [ (PUBMED:7519375) (PUBMED:9660801) ] of IGFBP-3 and -5. IGFBPs are unusually pleiotropic molecules. Like other binding proteins, IGFBP can prolong the half-life of IGFs via high affinity binding of the ligands. In addition to functioning as simple carrier proteins, serum IGFBPs also serve to regulate the endocrine and paracrine/autocrine actions of IGF by modulating the IGF available to bind to signalling IGF-I receptors [ (PUBMED:12379487) (PUBMED:12379489) ]. Furthermore, IGFBPs can function as growth modulators independent of IGFs. For example, IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs [ (PUBMED:11874691) ]. The binding of IGFBP to its putative receptor on the cell membrane may stimulate the signalling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBP-1 and -2, but not other IGFBPs, contain a C-terminal Arg-Gly-Asp integrin-binding motif. Thus, IGFBP-1 can also stimulate cell migration of CHO and human trophoblast cells through an action mediated by alpha 5 beta 1 integrin [ (PUBMED:7504269) ]. Finally, IGFBPs transported into the nucleus (via the nuclear localisation signal) may also exert IGF-independent effects by transcriptional activation of genes. This domain is the C-terminal domain of insulin-like growth factor II proteins (IGF-2, also see IPR004825 ) in vertebrates and seems to represent the E-peptide [ (PUBMED:8215015) (PUBMED:12324491) ].

PFAM accession number:

PF08365

Interpro abstract (IPR013576):

The insulin family of proteins groups together several evolutionarily related active peptides [ (PUBMED:6107857) ]: these include insulin [ (PUBMED:6243748) (PUBMED:503234) ], relaxin [ (PUBMED:10601981) (PUBMED:8735594) ], insect prothoracicotropic hormone (bombyxin) [ (PUBMED:8683595) ], insulin-like growth factors (IGF1 and IGF2) [ (PUBMED:2036417) (PUBMED:1319992) ], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [ (PUBMED:2036417) (PUBMED:1319992) (PUBMED:9141131) ]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain.

Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver [ (PUBMED:6243748) ]. Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth [ (PUBMED:6243748) ].

Insulin is synthesised as a prepropeptide from which an endoplasmic reticulum-targeting sequence is cleaved to yield proinsulin. The sequence of prosinsulin contains 2 well-conserved regions (designated A and B), separated by an intervening connecting region (C), which is variable between species [ (PUBMED:503234) ]. The connecting region is cleaved, liberating the active protein, which contains the A and B chains, held together by 2 disulphide bonds [ (PUBMED:503234) ].

Insulin-like Growth Factor Binding Proteins (IGFBP) are a group of vertebrate secreted proteins, which bind to IGF-I and IGF-II with high affinity and modulate the biological actions of IGFs. The IGFBP family has six distinct subgroups, IGFBP-1 through 6, based on conservation of gene (intron-exon) organisation, structural similarity, and binding affinity for IGFs. Across species, IGFBP-5 exhibits the most sequence conservation, while IGFBP-6 exhibits the least sequence conservation. The IGFBPs contain inhibitor domain homologues, which are related to MEROPS protease inhibitor family I31 (equistatin, clan IX).

All IGFBPs share a common domain architecture ( IPR000867 : IPR000716 ). While the N-terminal ( IPR000867 IGF binding protein domain), and the C-terminal ( IPR000716 thyroglobulin type-1 repeat) domains are conserved across vertebrate species, the mid-region is highly variable with respect to protease cleavage sites and phosphorylation and glycosylation sites. IGFBPs contain 16-18 conserved cysteines located in the N-terminal and the C-terminal regions, which form 8-9 disulphide bonds [ (PUBMED:11874691) ].

As demonstrated for human IGFBP-5, the N terminus is the primary binding site for IGF. This region, comprised of Val49, Tyr50, Pro62 and Lys68-Leu75, forms a hydrophobic patch on the surface of the protein [ (PUBMED:9822601) ]. The C terminus is also required for high affinity IGF binding, as well as for binding to the extracellular matrix [ (PUBMED:9725901) ] and for nuclear translocation [ (PUBMED:7519375) (PUBMED:9660801) ] of IGFBP-3 and -5.

IGFBPs are unusually pleiotropic molecules. Like other binding proteins, IGFBP can prolong the half-life of IGFs via high affinity binding of the ligands. In addition to functioning as simple carrier proteins, serum IGFBPs also serve to regulate the endocrine and paracrine/autocrine actions of IGF by modulating the IGF available to bind to signalling IGF-I receptors [ (PUBMED:12379487) (PUBMED:12379489) ]. Furthermore, IGFBPs can function as growth modulators independent of IGFs. For example, IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs [ (PUBMED:11874691) ]. The binding of IGFBP to its putative receptor on the cell membrane may stimulate the signalling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBP-1 and -2, but not other IGFBPs, contain a C-terminal Arg-Gly-Asp integrin-binding motif. Thus, IGFBP-1 can also stimulate cell migration of CHO and human trophoblast cells through an action mediated by alpha 5 beta 1 integrin [ (PUBMED:7504269) ]. Finally, IGFBPs transported into the nucleus (via the nuclear localisation signal) may also exert IGF-independent effects by transcriptional activation of genes.

This domain is the C-terminal domain of insulin-like growth factor II proteins (IGF-2, also see IPR004825 ) in vertebrates and seems to represent the E-peptide [ (PUBMED:8215015) (PUBMED:12324491) ].

This is a PFAM domain. For full annotation and more information, please see the PFAM entry IGF2_C