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Title: Conformational Dynamics of the Soluble and Membrane-Bound Forms of Interleukin-1 Receptor Type-1: Insights into Linker Flexibility and Domain Orientation
Authors: Luís, João P. 
Mata, Ana I. 
Simões, Carlos J. V. 
Brito, Rui M. M. 
Keywords: interleukin-1; interleukin-1 receptor type 1; flexible linker; molecular dynamics
Issue Date: 26-Feb-2022
Project: FCT - Ph.D. grant PD/BD/135292/2017 
FCT - Ph.D. grant PD/BD/135289/2017 
FCT - UID/QUI/00313/2019 
FCT - CPCA/A0/7316/2020 
Serial title, monograph or event: International Journal of Molecular Sciences
Volume: 23
Issue: 5
Abstract: Interleukin-1 receptor type 1 (IL-1R1) is a key player in inflammation and immune responses. This receptor regulates IL-1 activity in two forms: as a membrane-bound form and as a soluble ectodomain. The details and differences between the conformational dynamics of the membrane-bound and the soluble IL-1R1 ectodomains (ECDs) remain largely elusive. Here, we study and compare the structural dynamics of the soluble and membrane-bound IL-1R1-ECDs using molecular dynamics (MD) simulations, focusing on the flexible interdomain linker of the ECD, as well as the spatial rearrangements between the Ig-like domains of the ECD. To explore the membrane-bound conformations, a full-length IL-1R1 structural model was developed and subjected to classical equilibrium MD. Comparative analysis of multiple MD trajectories of the soluble and the membrane-bound IL-1R1-ECDs reveals that (i) as somewhat expected, the extent of the visited "open-to-closed" transitional states differs significantly between the soluble and membrane-bound forms; (ii) the soluble form presents open-closed transitions, sampling a wider rotational motion between the Ig-like domains of the ECD, visiting closed and "twisted" conformations in higher extent, whereas the membrane-bound form is characterized by more conformationally restricted states; (iii) interestingly, the backbone dihedral angles of residues Glu202, Glu203 and Asn204, located in the flexible linker, display the highest variations during the transition between discrete conformational states detected in IL-1R1, thus appearing to work as the "central wheel of a clock's movement". The simulations and analyses presented in this contribution offer a deeper insight into the structure and dynamics of IL-1R1, which may be explored in a drug discovery setting.
ISSN: 1422-0067
DOI: 10.3390/ijms23052599
Rights: openAccess
Appears in Collections:I&D CQC - Artigos em Revistas Internacionais

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