Chemical synthesis of human protein S thrombin-sensitive module and first epidermal growth factor module

Biopolymers
T M HackengJ H Griffin

Abstract

Human plasma protein S is a nonenzymatic cofactor for activated protein C (APC) in the inactivation of coagulation factors Va and VIIIa, and helps to provide an essential negative feedback on blood coagulation. Previous indirect evidence suggested that the thrombin-sensitive region (TSR: residues 47-75, 1 disulfide) and the first epidermal growth factorlike region (EGF1: residues 76-116, 3 disulfides) of protein S may be functionally important for expression of its APC cofactor activity. To study the functional importance of these modules directly, access to the isolated TSR and EGF1 modules would be preferred. Recombinant expression of protein S intact TSR and correctly folded EGF1 has not been possible. Here we describe the synthesis of both TSR and EGF1 modules by stepwise solid phase peptide synthesis using the in situ neutralization/2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluron ium hexafluorophosphate activation procedure for tert-butoxycarbonyl chemistry. For the TSR, correct intramodular disulfide bonding was confirmed. To overcome folding difficulties with the EGF1, a two-step oxidation procedure was used in which the cysteines involved in the middle, crossing, disulfide bond (Cys85-Cys102) remained protected with ac...Continue Reading

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Citations

May 8, 1999·The Journal of Peptide Research : Official Journal of the American Peptide Society·G MoynaA I Scott
Dec 6, 2000·Proceedings of the National Academy of Sciences of the United States of America·T M HackengJ H Griffin
Sep 12, 2008·The Journal of Biological Chemistry·Subramanian YegneswaranJohn H Griffin
Sep 21, 2007·Journal of Peptide Science : an Official Publication of the European Peptide Society·Taeko KakizawaYoshiaki Kiso
Mar 10, 2019·Protein Science : a Publication of the Protein Society·Jean A BoutinHubert Vaudry
Jul 10, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·Mette Husbyn, Alan Cuthbertson
Jun 23, 2000·The Journal of Peptide Research : Official Journal of the American Peptide Society·T J ZamborelliM A Jarosinski
Oct 21, 2004·The Journal of Biological Chemistry·Miquel Vila-PerellóDavid Andreu
Jan 20, 2006·Journal of Medicinal Chemistry·Miquel Vila-PerellóDavid Andreu
Jul 6, 2021·Current Opinion in Hematology·Rinku Majumder, Tina Nguyen

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