The Flexible, Extended Coil of the PDZ-Binding Motif of the Three Deadly Human Coronavirus E Proteins Plays a Role in Pathogenicity

Dewald Schoeman; Ruben Cloete; Burtram C Fielding

doi:10.3390/v14081707

The Flexible, Extended Coil of the PDZ-Binding Motif of the Three Deadly Human Coronavirus E Proteins Plays a Role in Pathogenicity

Viruses. 2022 Aug 2;14(8):1707. doi: 10.3390/v14081707.

Authors

Dewald Schoeman¹, Ruben Cloete², Burtram C Fielding¹

Affiliations

¹ Molecular Biology and Virology Research Laboratory, Department of Medical Biosciences, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa.
² South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa.

Abstract

The less virulent human (h) coronaviruses (CoVs) 229E, NL63, OC43, and HKU1 cause mild, self-limiting respiratory tract infections, while the more virulent SARS-CoV-1, MERS-CoV, and SARS-CoV-2 have caused severe outbreaks. The CoV envelope (E) protein, an important contributor to the pathogenesis of severe hCoV infections, may provide insight into this disparate severity of the disease. We, therefore, generated full-length E protein models for SARS-CoV-1 and -2, MERS-CoV, HCoV-229E, and HCoV-NL63 and docked C-terminal peptides of each model to the PDZ domain of the human PALS1 protein. The PDZ-binding motif (PBM) of the SARS-CoV-1 and -2 and MERS-CoV models adopted a more flexible, extended coil, while the HCoV-229E and HCoV-NL63 models adopted a less flexible alpha helix. All the E peptides docked to PALS1 occupied the same binding site and the more virulent hCoV E peptides generally interacted more stably with PALS1 than the less virulent ones. We hypothesize that the increased flexibility of the PBM in the more virulent hCoVs facilitates more stable binding to various host proteins, thereby contributing to more severe disease. This is the first paper to model full-length 3D structures for both the more virulent and less virulent hCoV E proteins, providing novel insights for possible drug and/or vaccine development.

Keywords: HADDOCK; PALS1; PDZ-binding motif (PBM); SARS-CoV-2; docking; envelope protein; homology-based modelling; human coronaviruses; pathogenesis; protein-protein interaction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
Coronavirus 229E, Human*
Coronavirus NL63, Human*
Coronavirus OC43, Human*
Humans
Middle East Respiratory Syndrome Coronavirus*
SARS-CoV-2
Virulence

Grants and funding

D.S. was funded by the National Research Foundation (NRF) of South Africa and, the Poliomyelitis Research Foundation (PRF) of South Africa [17/53]. R.C. was funded by the PRF of South Africa [19/06] and the Department of Higher Education, next Generation of Academic Programme (nGAP) in the form of full-time academic positions and salaries. B.C.F. received funding from the UWC Senate Research Fund and the NRF of South Africa. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors, and therefore, the NRF and PRF do not accept any liability in regard thereto.