Replacement of disulfides by amide bonds in the relaxin-like factor (RLF/INSL3) reveals a role for the A11-B10 link in transmembrane signaling

Biochemistry
E E Büllesbach, C Schwabe

Abstract

The relaxin-like factor (RLF) also named insulin-like 3 (INSL3) consists of two polypeptide chains linked by two interchain and one intrachain disulfide bond. RLF binds to its receptor (LGR8 also named RXFP2) through the B chain and initiates transmembrane communication by activating the adenylate cyclase through the N-terminal region of both chains. Cystine A11-B10 occupies a unique position on the molecular surface just outside the binding region and between the two signaling ports. We have synthesized an RLF analogue in which the disulfide A11-B10 was replaced by a peptide bond and found that cAMP production ceased while receptor binding was not affected. In contrast, replacing the disulfide A24-B22 by a peptide bond reduced potency proportional to the binding affinity and lowered efficacy to 65%, while replacing disulfide A10-A15 by a peptide bond reduced binding affinity to 32% and lowered potency to 7% but maintained 100% efficacy. The exceptional properties of the derivative bearing an A11-B10 isopeptide cross-link suggests that the disulfide has a special role in signal transduction. We propose that disulfide A11-B10 serves as an insulator between the two ports, whereas the amide functionality disturbs the signal transm...Continue Reading

References

Jul 7, 1995·The Journal of Biological Chemistry·E E Büllesbach, C Schwabe
Jul 31, 1999·The Journal of Biological Chemistry·E E Büllesbach, C Schwabe
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·T M HackengP E Dawson
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Dec 19, 2003·Nucleic Acids Research·Lukasz SalwinskiDavid Eisenberg
Feb 15, 2005·The Journal of Biological Chemistry·Erika E Büllesbach, Christian Schwabe
Jul 18, 2006·The Journal of Biological Chemistry·Erika E Büllesbach, Christian Schwabe
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Aug 7, 2007·Biochemistry·Erika E Büllesbach, Christian Schwabe
Jul 5, 2011·Current Opinion in Structural Biology·Xavier Deupi, Jörg Standfuss

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Citations

Dec 19, 2013·PloS One·Fazel ShabanpoorMohammed Akhter Hossain
Mar 10, 2016·Organic & Biomolecular Chemistry·Tessa LühmannBradley L Pentelute
Jul 18, 2012·Regulatory Peptides·Indunil N PathiranaHiromichi Tamada
Dec 7, 2016·British Journal of Pharmacology·Nitin A PatilMohammed Akhter Hossain
Mar 4, 2015·Organic & Biomolecular Chemistry·Geoffrey M WilliamsMargaret A Brimble
Jul 28, 2017·Chemistry : a European Journal·Alessandro GoriSilvia Rinaldi

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