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Heteromerization As a Mechanism Modulating the Affinity of the ACE2 Receptor to the Receptor Binding Domain of SARS-CoV-2 Spike Protein

Author(s):

Diego Guidolin*, Cinzia Tortorella, Deanna Anderlini, Manuela Marcoli, Guido Maura and Luigi F. Agnati   Pages 1 - 10 ( 10 )

Abstract:


Background: Angiotensin-converting enzyme 2 (ACE2) is primarily involved in the maturation of angiotensin. It also represents the main receptor for the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) that caused a serious epidemic COVID-19. Available evidence indicates that at the cell membrane, ACE2 can form heteromeric complexes with other membrane proteins, including the amino acid transporter B0 AT1 and G protein-coupled receptors (GPCR).

Objective: It is well known that during the formation of quaternary structures, the configuration of every single monomer is re-shaped by its interaction pattern in the macromolecular complex. Therefore, it can be hypothesized that the affinity of ACE2 to the viral receptor-binding domain (RBD), when in a heteromeric complex, may depend on the associated partner.

Methods: By using established docking and molecular dynamics procedures, the reshaping of monomer was explored in silico to predict possible heterodimeric structures between ACE2 and GPCR, such as angiotensin and bradykinin receptors. The associated possible changes in the binding affinity between the viral RBD and ACE2 when in the heteromeric complexes were also estimated.

Results and Conclusion: The results provided support to the hypothesis that the heteromerization state of ACE2 may modulate its affinity to the viral RBD. If experimentally confirmed, ACE2 heteromerization may contribute to explain the observed differences in susceptibility to virus infection among individuals and to devise new therapeutic opportunities.

Keywords:

Angiotensin-converting enzyme 2, protein-protein interactions, heteromers, coronavirus, docking, molecular modeling.

Affiliation:

Deptartment of Neuroscience, University of Padova, 35121 Padova, Deptartment of Neuroscience, University of Padova, 35121 Padova, Centre for Sensorimotor Performance, The University of Queensland, 4072 Brisbane, Department of Pharmacy and Center of Excellence for Biomedical Research, University of Genova, 16126 Genova, Department of Pharmacy and Center of Excellence for Biomedical Research, University of Genova, 16126 Genova, Department of Neuroscience, Karolinska Institutet, 17177 Stockholm



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