Journal article
A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin
JG Menting, J Gajewiak, CA MacRaild, DHC Chou, MM Disotuar, NA Smith, C Miller, J Erchegyi, JE Rivier, BM Olivera, BE Forbes, BJ Smith, RS Norton, H Safavi-Hemami, MC Lawrence
Nature Structural and Molecular Biology | NATURE PUBLISHING GROUP | Published : 2016
DOI: 10.1038/nsmb.3292
Abstract
Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor and assembly of the hormone's hexameric storage form. Removal of this segment (residues B23-B30) in human insulin results in substantial loss of receptor affinity. Here, we found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling. Con-Ins G1 thus is a naturally occurring B-chain-minimized mimetic of human ins..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
R.S.N. acknowledges fellowship support from the National Health and Medical Research Council of Australia (NHMRC). N.A.S. acknowledges receipt of an Australian Postgraduate Award scholarship. This work was supported in part by National Institutes of Health grants GM 48677 (to B.M.O. and J.E.R., a subcontractor at Sentia Medical Sciences), by NHMRC Project Grant APP1058233 (to M.C.L.) and by the Utah Science and Technology Initiative (USTAR, to D.H.-C.C.). H.S.-H. acknowledges fellowship support from the European Commission (CONBIOS 330486). Aspects of this work were made possible through Victorian State Government Operational Infrastructure Support, the Australian Government NHMRC IRIISS and a pilot grant from the University of Utah Diabetes and Metabolism Center. We thank A. Morrione (Thomas Jefferson University) for providing cells. Part of this research was undertaken on the MX2 beandine at the Australian Synchrotron (Victoria, Australia).