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Structural characterization of the thermal unfolding pathway of human VEGFR1 D2 domain.

Authors
  • Diana, Donatella1
  • Di Stasi, Rossella1
  • García-Viñuales, Sara2
  • De Rosa, Lucia1
  • Isernia, Carla3
  • Malgieri, Gaetano3
  • Milardi, Danilo2
  • D'Andrea, Luca D4
  • Fattorusso, Roberto3
  • 1 Istituto di Biostrutture e Bioimmagini, CNR, Napoli, Italy. , (Italy)
  • 2 Istituto di Cristallografia, CNR, Catania, Italy. , (Italy)
  • 3 Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli', Caserta, Italy. , (Italy)
  • 4 Istituto di Scienze e Tecnologie Chimiche 'Giulio Natta', CNR, Milano, Italy. , (Italy)
Type
Published Article
Journal
FEBS Journal
Publisher
Wiley (Blackwell Publishing)
Publication Date
Mar 01, 2022
Volume
289
Issue
6
Pages
1591–1602
Identifiers
DOI: 10.1111/febs.16246
PMID: 34689403
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Folding stability is a crucial feature of protein evolution and is essential for protein functions. Thus, the comprehension of protein folding mechanisms represents an important complement to protein structure and function, crucial to determine the structural basis of protein misfolding. In this context, thermal unfolding studies represent a useful tool to get a molecular description of the conformational transitions governing the folding/unfolding equilibrium of a given protein. Here, we report the thermal folding/unfolding pathway of VEGFR1D2, a member of the immunoglobulin superfamily by means of a high-resolution thermodynamic approach that combines differential scanning calorimetry with atomic-level unfolding monitored by NMR. We show how VEGFR1D2 folding is driven by an oxidatively induced disulfide pairing: the key event in the achievement of its functional structure is the formation of a small hydrophobic core that surrounds a disulfide bridge. Such a 'folding nucleus' induces the cooperative transition to the properly folded conformation supporting the hypothesis that a disulfide bond can act as a folding nucleus that eases the folding process. © 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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