An in silico approach to determine inter-subunit affinities in human septin complexes

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dc.contributor.authorGrupp, Benjaminen
dc.contributor.authorLemkul, Justin A.en
dc.contributor.authorGronemeyer, Thomasen
dc.date.accessioned2024-01-22T19:20:54Zen
dc.date.available2024-01-22T19:20:54Zen
dc.date.issued2023-03-09en
dc.description.abstractThe septins are a conserved family of filament-forming guanine nucleotide binding proteins, often named the fourth component of the cytoskeleton. Correctly assembled septin structures are required for essential intracellular processes such as cytokinesis, vesicular transport, polarity establishment, and cellular adhesion. Structurally, septins belong to the P-Loop NTPases but they do not mediate signals to effectors through GTP binding and hydrolysis. GTP binding and hydrolysis are believed to contribute to septin complex integrity, but biochemical approaches addressing this topic are hampered by the stability of septin complexes after recombinant expression and the lack of nucleotide-depleted complexes. To overcome this limitation, we used a molecular dynamics-based approach to determine inter-subunit binding free energies in available human septin dimer structures and in their apo forms, which we generated in silico. The nucleotide in the GTPase active subunits SEPT2 and SEPT7, but not in SEPT6, was identified as a stabilizing element in the G interface. Removal of GDP from SEPT2 and SEPT7 results in flipping of a conserved Arg residue and disruption of an extensive hydrogen bond network in the septin unique element, concomitant with a decreased inter-subunit affinity. Based on these findings we propose a singular “lock-hydrolysis” mechanism stabilizing human septin filaments.en
dc.description.versionAccepted versionen
dc.format.extentPages 141-152en
dc.format.extent12 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1002/cm.21749en
dc.identifier.eissn1949-3592en
dc.identifier.issn1949-3584en
dc.identifier.issue7-8en
dc.identifier.orcidLemkul, Justin [0000-0001-6661-8653]en
dc.identifier.pmid36843207en
dc.identifier.urihttps://hdl.handle.net/10919/117574en
dc.identifier.volume80en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36843207en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectbiophysicsen
dc.subjectmolecular dynamicsen
dc.subjectseptinsen
dc.subject.meshCytoskeletonen
dc.subject.meshHumansen
dc.subject.meshGTP-Binding Proteinsen
dc.subject.meshNucleotidesen
dc.subject.meshGuanosine Triphosphateen
dc.subject.meshSeptinsen
dc.titleAn in silico approach to determine inter-subunit affinities in human septin complexesen
dc.title.serialCytoskeletonen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2023-02-22en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen

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