Biophysical and structural characterization of a folded core domain within the proregion of growth and differentiation factor‐5. (26th September 2014)

• Record Type: Journal Article
• Authors: Thieme, Tino; Patzschke, Rica; Job, Florian; Liebold, Jens; Seemann, Petra; Lilie, Hauke; Balbach, Jochen; Schwarz, Elisabeth
• Is Part Of: FEBS journal. Volume 281:Number 21(2014)
• Page Start: 4866
• Page End: 4877
• Publication Date: 2014-09-26
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.13025
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs13025-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The structure and function(s) of the very large proregions of the transforming growth factor‐β structure family are known in only a few cases. The proregion of growth and differentiation factor (GDF)5 comprises 354 residues. GDF5 therefore belongs to the group of those growth factors with the largest proregions. Here, we report a biophysical analysis of the proform (proGDF5) and the separate proregion. In the absence of the mature part, the proregion folds reversibly to form a monomeric polypeptide that is stabilized by an intramolecular disulfide bond. In the context of the mature part, i.e. in proGDF5, the proregion shows increased thermodynamic stability and contains a higher proportion of secondary structural elements than in its isolated form. A subdomain within the proregion represents a well‐folded structure as monitored via biophysical analysis and NMR spectroscopy. Furthermore, two point mutations that are associated with skeletal malformations lead to reduced thermodynamic stability, which is interpreted on the basis of a homology model with the structure of the related latency‐associated peptide, representing the proregion of transforming growth factor‐β1.</p> </abstract>