pH-induced conformational transitions of a molten-globule-like state of the inhibitory prodomain of furin: implications for zymogen activation

Protein Science : a Publication of the Protein Society
Surajit BhattacharjyaFeng Ni

Abstract

The endoprotease furin, which belongs to the family of mammalian proprotein convertase (PC), is synthesized as a zymogen with an N-terminal, 81-residue inhibitory prodomain. It has been shown that the proenzyme form of furin undergoes a multistep 'autocatalytic' removal of the prodomain at the C-terminal side of the two consensus sites, R(78)-T-K-R(81) approximately and R(44)-G-V-T-K-R(49) approximately. The furin-mediated cleavage at R(44)-G-V-T-K-R(49) approximately, in particular, is significantly accelerated in an 'acidic' environment. Here, we show that under neutral pH conditions, the inhibitory prodomain of furin is partially folded and undergoes conformational exchanges as indicated by extensive broadening of the NMR spectra. Presence of many ring-current shifted methyl resonances suggests that the partially folded state of the prodomain may still possess a 'semirigid' protein core with specific packing interactions among amino acid side chains. Measurements of the hydrodynamic radii and compaction factors indicate that this partially folded state is significantly more compact than a random chain. The conformational stability of the prodomain appears to be pH sensitive, in that the prodomain undergoes an unfolding trans...Continue Reading

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Citations

Jul 4, 2002·Journal of Molecular Biology·Michael A TangreaJohn Orban
May 10, 2008·Endocrinology·Sang-Nam Lee, Iris Lindberg
Jul 12, 2008·Proteins·Anirban BhuniaSurajit Bhattacharjya
May 5, 2007·Biopolymers·Surajit BhattacharjyaFeng Ni
Jun 10, 2003·Nature Structural Biology·Stefan HenrichManuel E Than
Apr 8, 2006·The Journal of Biological Chemistry·Sylvain F FeliciangeliGary Thomas
May 16, 2014·Chembiochem : a European Journal of Chemical Biology·Mukesh Mahajan, Surajit Bhattacharjya
May 9, 2013·The Journal of Biological Chemistry·Danielle M WilliamsonUjwal Shinde
Aug 17, 2020·International Journal of Molecular Sciences·Surajit Bhattacharjya, Suzana K Straus
Oct 11, 2017·Biochimica Et Biophysica Acta. Biomembranes·Mukesh MahajanSurajit Bhattacharjya
Nov 12, 2009·Biochemical and Biophysical Research Communications·Prerna N DomadiaSurajit Bhattacharjya

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