Oxidation State Dependent Conformational Changes of HMGB1 Regulate the Formation of the CXCL12/HMGB1 Heterocomplex

Enrico M A Fassi; Jacopo Sgrignani; Gianluca D'Agostino; Valentina Cecchinato; Maura Garofalo; Giovanni Grazioso; Mariagrazia Uguccioni; Andrea Cavalli

doi:10.1016/j.csbj.2019.06.020

Oxidation State Dependent Conformational Changes of HMGB1 Regulate the Formation of the CXCL12/HMGB1 Heterocomplex

Comput Struct Biotechnol J. 2019 Jun 21:17:886-894. doi: 10.1016/j.csbj.2019.06.020. eCollection 2019.

Authors

Enrico M A Fassi¹, Jacopo Sgrignani¹, Gianluca D'Agostino¹, Valentina Cecchinato¹, Maura Garofalo^{1

2}, Giovanni Grazioso³, Mariagrazia Uguccioni^{1

4}, Andrea Cavalli^{1

5}

Affiliations

¹ Institute for Research in Biomedicine, Università della Svizzera Italiana, CH-6500 Bellinzona, Switzerland.
² University of Lausanne (UNIL), CH-1015, Lausanne, Switzerland.
³ Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milan, Italy.
⁴ Humanitas University, Department of Biomedical Sciences, 20090, Pieve Emanuele, Milan, Italy.
⁵ Swiss Institute of Bioinformatics, Lausanne, Switzerland.

Abstract

High-mobility Group Box 1 (HMGB1) is an abundant protein present in all mammalian cells and involved in several processes. During inflammation or tissue damage, HMGB1 is released in the extracellular space and, depending on its redox state, can form a heterocomplex with CXCL12. The heterocomplex acts exclusively via the chemokine receptor CXCR4 enhancing leukocyte recruitment. Here, we used multi-microsecond molecular dynamics (MD) simulations to elucidate the effect of the disulfide bond on the structure and dynamics of HMGB1. The results of the MD simulations show that the presence or lack of the disulfide bond between Cys23 and Cys45 modulates the conformational space explored by HMGB1, making the reduced protein more suitable to form a complex with CXCL12.

Keywords: CXCL12; CXCL12, C-X-C motif chemokine 12; CXCR4, C-X-C chemokine receptor type 4; Conformational ensemble; HMGB1; HMGB1, High-mobility Group Box 1; MD, Molecular dynamics; Molecular dynamics; Protein-protein docking; RMSD, Root mean square deviation; RoG, Radius of gyration; SASA, Solvent accessible surface area; TLR2 or TLR4, Toll-like Receptor 2 or 4; ds-HMGB1, Disulfide High-mobility Group Box 1; fr-HMGB1, Full reduced High-mobility Group Box 1.