JMIR Publications

ABSTRACT

Background:

The protein A Disintegrin and Metalloprotease Domain-Containing 17 (ADAM-17), also called TACE, generally plays an important role in the cleavage of the Pro-Leu-Ala-Gln-Ala-/-Val-Arg-Ser-Ser-Ser sequence in the membrane-bound precursor of tumor necrosis factor alpha (TNF-α). This cleavage process has significant implications for inflammatory and immune responses, and recent studies suggest a role for ADAM-17 variants in SARS-CoV-2 infection.

Objective:

To identify the most deleterious missense variants of ADAM-17 that impact protein stability, structure, and function, and to assess specific variants potentially involved in SARS-CoV-2 infection.

Methods:

A bioinformatics approach was employed using tools including SIFT, PolyPhen2.0, PROVEAN, PANTHER, SNP&GO, PhD-SNP, Mutation Assessor, SNAP2, MUpro, I-Mutant, iStable, Interpro, Sparks-x, PROCHECK, PyMol, Project HOPE, ConSurf, and Swiss-Model. Missense variants of ADAM-17 were collected from the Ensembl database for analysis.

Results:

Seven nonsynonymous SNPs (P556L, G550D, V483A, G479E, G349E, T339P, and D232E) were identified as high-risk pathogenic by all prediction tools, and these variants found to have deleterious effects on the stability, structure and function of the ADAM-17 protein. Additionally, four missense variants (Q658H, D657G, D654N, F652L) in positions related to SARS-CoV-2 infection exhibited high conservation scores and were predicted to be deleterious, suggesting they play an important role in SARS-CoV-2 infection.

Conclusions:

Specific missense variants of ADAM-17 are predicted to be highly pathogenic, affecting protein stability and function. Certain variants play important role in SARS-CoV-2 infection, these variants indicate that ADAM-17 may play an important role in viral pathogenesis.