Genetic variants in TMPRSS2 and Structure of SARS-CoV-2 spike glycoprotein and TMPRSS2 complex

AbstractSARS-CoV-2, a highly transmittable pathogen has infected over 3.8 million people around the globe. The spike glycoprotein of SARS-CoV-2 engages host ACE2 for adhesion, TMPRSS2 for activation and entry. With the aid of whole-exome sequencing, we report a variant rs12329760 in TMPRSS2 gene and its mutant V160M, which might impede viral entry. Furthermore, we identified TMPRSS2 cleavage sites in S2 domain of spike glycoprotein and report the structure of TMPRSS2 in complex with spike glycoprotein. We also report the structures of protease inhibitors in complex with TMPRSS2, which could hamper the interaction with spike protein. These findings advance our understanding on the role of TMPRSS2 and in the development of potential therapeutics.

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The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

10.1101/2020.06.09.142877 ◽

2020 ◽

Cited By ~ 1

Author(s):

Baofu Qiao ◽

Monica Olvera de la Cruz

Keyword(s):

Viral Entry ◽

Electrostatic Interactions ◽

Large Scale ◽

Cell Receptor ◽

Spike Protein ◽

Cleavage Sites ◽

Explicit Solvent ◽

Dynamics Simulations ◽

Positively Charged

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection.Abstract FigureTOC:The SARS-CoV-2 spike protein-ACE2 complex showing the polybasic cleavage sites

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Faculty Opinions recommendation of Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718194747.793488319 ◽

2013 ◽

Author(s):

Alon Keinan

Keyword(s):

Type 2 Diabetes ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome ◽

Coding Variants

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Exploration of the role of whole exome sequencing variants in -associated Parkinson disease

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2020.12.279 ◽

2021 ◽

Vol 132 (2) ◽

pp. S113

Author(s):

Elizabeth Geena Woo ◽

Frank Donovan ◽

Barbara Stubblefield ◽

Settara Chandrasekharappa ◽

Grisel Lopez ◽

...

Keyword(s):

Parkinson Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome

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Analysis workflow to assess de novo genetic variants from human whole-exome sequencing

STAR Protocols ◽

10.1016/j.xpro.2021.100383 ◽

2021 ◽

Vol 2 (1) ◽

pp. 100383

Author(s):

Nicholas S. Diab ◽

Spencer King ◽

Weilai Dong ◽

Garrett Allington ◽

Amar Sheth ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

De Novo ◽

Whole Exome ◽

Analysis Workflow

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Whole Exome Sequencing identifies the potential role of genes involved in p53 pathway in Nasopharyngeal Carcinoma from Northeast India

Gene ◽

10.1016/j.gene.2021.146099 ◽

2021 ◽

pp. 146099

Author(s):

Shaheen Laskar ◽

Raima Das ◽

Sharbadeb Kundu ◽

Amrita Saha ◽

Nilashis Nandi ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Potential Role ◽

Northeast India ◽

P53 Pathway ◽

Whole Exome

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Identification of rare genetic variants in Juvenile Idiopathic Arthritis using whole exome sequencing

Pediatric Rheumatology ◽

10.1186/1546-0096-13-s1-p144 ◽

2015 ◽

Vol 13 (S1) ◽

Author(s):

E Sanchez ◽

S Grandemange ◽

F Tran Mau-Them ◽

P Louis-Plence ◽

A Carbasse ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Whole Exome ◽

Rare Genetic Variants

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Whole-exome sequencing of non-metastatic anal squamous cell carcinoma: a prognostic genetic variants analysis

Annals of Oncology ◽

10.1093/annonc/mdz155.162 ◽

2019 ◽

Vol 30 ◽

pp. iv44

Author(s):

I. Ghanem ◽

L. Trilla ◽

A. Gámez ◽

M. Mendiola ◽

J. Maurel ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Squamous Cell ◽

Genetic Variants ◽

Anal Squamous Cell Carcinoma ◽

Whole Exome

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Investigation of the role of vitamin D metabolism in South African breast cancer patients using whole exome sequencing

The Breast ◽

10.1016/s0960-9776(19)30162-6 ◽

2019 ◽

Vol 44 ◽

pp. S36

Author(s):

A. Okunola ◽

R. Torrorey-Sawe ◽

K.J. Baatjes ◽

A.E. Zemlin ◽

R.T. Erasmus ◽

...

Keyword(s):

Breast Cancer ◽

Vitamin D ◽

Exome Sequencing ◽

Cancer Patients ◽

South African ◽

Whole Exome Sequencing ◽

Breast Cancer Patients ◽

Vitamin D Metabolism ◽

Whole Exome

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Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes

Human Genetics ◽

10.1007/s00439-020-02231-6 ◽

2020 ◽

Author(s):

Aldesia Provenzano ◽

Andrea La Barbera ◽

Mirko Scagnet ◽

Angelica Pagliazzi ◽

Giovanna Traficante ◽

...

Keyword(s):

Exome Sequencing ◽

Chromatin Remodeling ◽

Brain Mri ◽

Cranial Bone ◽

Genetic Syndromes ◽

Whole Exome ◽

Cerebellar Tonsillar Herniation ◽

Brain Magnetic Resonance Image

AbstractType 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

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