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Role of disulfide bonds for the structure and folding of proguanylin

Title data

Lauber, Thomas ; Schulz, Axel ; Rösch, Paul ; Marx, Ute C.:
Role of disulfide bonds for the structure and folding of proguanylin.
In: Biochemistry. Vol. 43 (2004) Issue 31 . - pp. 10050-10057.
ISSN 1520-4995
DOI: https://doi.org/10.1021/bi049667e

Abstract in another language

The intestinal peptide hormone guanylin circulates mainly as its corresponding prohormone of 94 amino acids and is the first identified endogenous ligand of intestinal guanylyl cyclase C. While the prohormone is biologically inactive, it is processed to the fully functional form with 15 amino acid residues corresponding to the COOH terminus of the precursor protein. In addition to this inactivation of the hormone region, the prosequence makes an essential contribution to the disulfide-coupled folding of the hormone. On the basis of the recently determined solution structure of proguanylin, explanations for these functions of the prosequence were found, indicating that interstrand contacts between the NH2-terminal beta-hairpin of the prosequence and the COOH-terminal hormone region are crucial for formation of the correct disulfide bonds of guanylin. To further investigate the role of individual disulfide bonds upon stabilization of the overall three-dimensional structure of proguanylin and to test the assumption of a direct effect of the prosequence on the structure of the hormone region, we studied the cysteine double mutant proteins proguanylin-C48S/C61S and proguanylin-C86S/C94S. Disulfide determination as well as CD and NMR spectroscopy of proguanylin-C48S/C61S reveals an essential function of the Cys48-Cys61 disulfide bond for the stability of the hydrophobic core and thereby for the stability of the overall three-dimensional structure of proguanylin. Furthermore, sequence specific resonance assignment of the second disulfide deletion mutant, proguanylin-C86S/C94S, and comparison of the NMR spectra of this protein with those of the wild-type protein demonstrate that the rigid helical core structure of proguanylin is not affected by the mutation. Additionally, analysis of the interstrand contacts between the termini reveals a direct effect of the prosequence on the conformation of the hormone region. On the basis of these results, we propose a cooperative mechanism that leads to formation of the correct disulfide pattern of guanylin.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors > Chair Biopolymers - Univ.-Prof. Dr. Paul Rösch
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biopolymers
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 28 Jan 2019 10:00
Last Modified: 16 May 2019 05:37
URI: https://eref.uni-bayreuth.de/id/eprint/47056