| Structural highlights
Disease
IGF2_HUMAN Epigenetic changes of DNA hypomethylation in IGF2 are a cause of Silver-Russell syndrome (SRS) [MIM:180860. A clinically heterogeneous condition characterized by severe intrauterine growth retardation, poor postnatal growth, craniofacial features such as a triangular shaped face and a broad forehead, body asymmetry, and a variety of minor malformations. The phenotypic expression changes during childhood and adolescence, with the facial features and asymmetry usually becoming more subtle with age.[1]
Function
IGF2_HUMAN The insulin-like growth factors possess growth-promoting activity. In vitro, they are potent mitogens for cultured cells. IGF-II is influenced by placental lactogen and may play a role in fetal development.[2] Preptin undergoes glucose-mediated co-secretion with insulin, and acts as physiological amplifier of glucose-mediated insulin secretion. Exhibits osteogenic properties by increasing osteoblast mitogenic activity through phosphoactivation of MAPK1 and MAPK3.[3]
Publication Abstract from PubMed
Insulin and insulin-like growth factors I and II are closely related protein hormones. Their distinct evolution has resulted in different yet overlapping biological functions, with insulin becoming a key regulator of metabolism, while IGF-I/II are major growth factors. Insulin and IGFs cross-bind with different affinities to closely related insulin receptor isoforms A and B (IR-A and IR-B) and IGF-I receptor (IGF-1R). Identification of structural determinants in IGFs and insulin that trigger their specific signaling pathways is of increasing importance in designing receptor specific analogs with potential therapeutic applications. Here, we developed a straightforward protocol for production of recombinant IGF-II and prepared six IGF-II analogs with IGF-I-like mutations. All modified molecules exhibit significantly reduced affinity towards IR-A, particularly the analogs with Pro-Gln insertion in the C-domain. Moreover, one of the analogs has enhanced binding affinity for IGF-1R due to a synergistic effect of the Pro-Gln insertion and Ser29Asn point mutation. Consequently, this analog has almost a 10-fold higher IGF-1R/IR-A binding specificity in comparison with native IGF-II. The established IGF-II purification protocol allowed for a cost-effective isotope labeling required for a detailed NMR structural characterization of IGF-II analogs that revealed a link between the altered binding behavior of selected analogs and conformational rearrangement of their C-domain.
Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain.,Hexnerova R, Krizkova K, Fabry M, Sieglova I, Kedrova K, Collinsova M, Ullrichova P, Srb P, Williams C, Crump MP, Tosner Z, Jiracek J, Veverka V, Zakova L J Biol Chem. 2016 Aug 10. pii: jbc.M116.741041. PMID:27510031[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bartholdi D, Krajewska-Walasek M, Ounap K, Gaspar H, Chrzanowska KH, Ilyana H, Kayserili H, Lurie IW, Schinzel A, Baumer A. Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. J Med Genet. 2009 Mar;46(3):192-7. doi: 10.1136/jmg.2008.061820. Epub 2008 Dec 9. PMID:19066168 doi:10.1136/jmg.2008.061820
- ↑ Cornish J, Callon KE, Bava U, Watson M, Xu X, Lin JM, Chan VA, Grey AB, Naot D, Buchanan CM, Cooper GJ, Reid IR. Preptin, another peptide product of the pancreatic beta-cell, is osteogenic in vitro and in vivo. Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E117-22. Epub 2006 Aug 15. PMID:16912056 doi:10.1152/ajpendo.00642.2005
- ↑ Cornish J, Callon KE, Bava U, Watson M, Xu X, Lin JM, Chan VA, Grey AB, Naot D, Buchanan CM, Cooper GJ, Reid IR. Preptin, another peptide product of the pancreatic beta-cell, is osteogenic in vitro and in vivo. Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E117-22. Epub 2006 Aug 15. PMID:16912056 doi:10.1152/ajpendo.00642.2005
- ↑ Hexnerova R, Krizkova K, Fabry M, Sieglova I, Kedrova K, Collinsova M, Ullrichova P, Srb P, Williams C, Crump MP, Tosner Z, Jiracek J, Veverka V, Zakova L. Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain. J Biol Chem. 2016 Aug 10. pii: jbc.M116.741041. PMID:27510031 doi:http://dx.doi.org/10.1074/jbc.M116.741041
|
