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Cytotoxic PSMα3 inhibits the aggregation of human insulin
Ist Teil von
Physical chemistry chemical physics : PCCP, 2024-05, Vol.26 (21), p.15587-15599
Erscheinungsjahr
2024
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
Phenol-soluble modulins (PSMs) are extracellular short amphipathic peptides secreted by the bacteria
Staphylococcus aureus
(
S. aureus
). They play an essential role in the bacterial lifecycle, biofilm formation, and stabilisation. From the PSM family, PSMα3 has been of special interest recently due to its cytotoxicity and highly stable α-helical conformation, which also remains in its amyloid fibrils. In particular, PSMα3 fibrils were shown to be composed of self-associating "sheets" of α-helices oriented perpendicular to the fibril axis, mimicking the architecture of canonical cross-β fibrils. Therefore, they were called cross-α-fibrils. PSMα3 was synthesised and verified for identity with wild-type sequences (
S. aureus
). Then, using several experimental techniques, we evaluated its propensity for
in vitro
aggregation. According to our findings, synthetic PSMα3 (which lacks the N-terminal formyl groups found in bacteria) does not form amyloid fibrils and maintains α-helical conformation in a soluble monomeric form for several days of incubation. We also evaluated the influence of PSMα3 on human insulin fibrillation
in vitro
, using a variety of experimental approaches in combination with computational molecular studies. First, it was shown that PSMα3 drastically inhibits the fibrillation of human insulin. The anti-fibrillation effect of PSMα3 was concentration-dependent and required a concentration ratio of PSMα3: insulin equal to or above 1 : 100. Molecular modelling revealed that PSMα3 most likely inhibits the production of insulin primary nuclei by competing for residues involved in its dimerization.
An α-helical PSMα3 considerably inhibits the fibrillation of human insulin
in vitro
. The anti-amyloidogenic effect of PSMα3 is concentration-dependent. PSMα3 inhibits insulin aggregation through the suppression of primary nucleation.
Sprache
–
Identifikatoren
ISSN: 1463-9076
eISSN: 1463-9084
DOI: 10.1039/d4cp00669k
Titel-ID: cdi_rsc_primary_d4cp00669k
Format
–
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