dc.contributor.author
Panina, Irina
dc.contributor.author
Krylov, Nikolay
dc.contributor.author
Gadalla, Mohamed Rasheed
dc.contributor.author
Aliper, Elena
dc.contributor.author
Kordyukova, Larisa
dc.contributor.author
Veit, Michael
dc.contributor.author
Chugunov, Anton
dc.contributor.author
Efremov, Roman
dc.date.accessioned
2022-08-04T13:01:34Z
dc.date.available
2022-08-04T13:01:34Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/35734
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-35449
dc.description.abstract
Lipid modification of viral proteins with fatty acids of different lengths (S-acylation) is crucial for virus pathogenesis. The reaction is catalyzed by members of the DHHC family and proceeds in two steps: the autoacylation is followed by the acyl chain transfer onto protein substrates. The crystal structure of human DHHC20 (hDHHC20), an enzyme involved in the acylation of S-protein of SARS-CoV-2, revealed that the acyl chain may be inserted into a hydrophobic cavity formed by four transmembrane (TM) α-helices. To test this model, we used molecular dynamics of membrane-embedded hDHHC20 and its mutants either in the absence or presence of various acyl-CoAs. We found that among a range of acyl chain lengths probed only C16 adopts a conformation suitable for hDHHC20 autoacylation. This specificity is altered if the small or bulky residues at the cavity’s ceiling are exchanged, e.g., the V185G mutant obtains strong preferences for binding C18. Surprisingly, an unusual hydrophilic ridge was found in TM helix 4 of hDHHC20, and the responsive hydrophilic patch supposedly involved in association was found in the 3D model of the S-protein TM-domain trimer. Finally, the exchange of critical Thr and Ser residues in the spike led to a significant decrease in its S-acylation. Our data allow further development of peptide/lipid-based inhibitors of hDHHC20 that might impede replication of Corona- and other enveloped viruses.
en
dc.format.extent
21 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
palmitoylation
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::616 Krankheiten
dc.title
Molecular Dynamics of DHHC20 Acyltransferase Suggests Principles of Lipid and Protein Substrate Selectivity
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
5091
dcterms.bibliographicCitation.doi
10.3390/ijms23095091
dcterms.bibliographicCitation.journaltitle
International Journal of Molecular Sciences
dcterms.bibliographicCitation.number
9
dcterms.bibliographicCitation.originalpublishername
MDPI
dcterms.bibliographicCitation.volume
23
dcterms.bibliographicCitation.url
https://doi.org/10.3390/ijms23095091
refubium.affiliation
Veterinärmedizin
refubium.affiliation.other
Institut für Virologie
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1422-0067