| Title: |
Prostate cancer risk-associated single-nucleotide polymorphisms impact the conformational dynamics of prostate-specific antigen |
| Authors: |
Srinivasan, Srilakshmi; Hayes, Brooke K.; Costa, Maurício G. S.; Riley, Blake T.; Wilson, Emily; Marijanovic, Emilia M.; Kass, Itamar; Koistinen, Hannu; Hoke, David E.; Clements, Judith A.; Buckle, Ashley M.; Batra, Jyotsna |
| Contributors: |
Department of Clinical Chemistry and Hematology; HUS Abdominal Center; Hannu Kalevi Koistinen / Principal Investigator |
| Publisher Information: |
BioMed Central |
| Publication Year: |
2026 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Conformational dynamics; Kallikrein-related peptidase; Molecular dynamic simulations; Prostate cancer; Prostate-specific antigen; Protein stability; Single-nucleotide polymorphism; Cancers |
| Description: |
BackgroundTwo non-synonymous single-nucleotide polymorphisms (SNPs) rs61752561 (D95N substitution) and rs17632542 (I163T substitution) in the KLK3 gene encoding prostate-specific antigen (PSA), a chymotrypsin-like serine protease, are associated with prostate cancer risk and have been shown to reduce the activity of PSA. However, the structural impact of these SNPs on PSA, which may underlie the observed risk associations and functional alterations, has not been fully explored.ResultsComputational modelling predicted that the variants D95N and I163T do not cause drastic structural changes in PSA. However, molecular dynamics simulations suggested that while the two prominent loops of wild-type PSA remain tethered to their initial conformations over 500 ns of simulation, they are disrupted in both variants, leading to increased loop dynamics. Frustration analysis, normal mode analysis (NMA) and perturbation response scanning identified dynamic links between mutation sites and increased loop dynamics that trigger long-range conformational changes, disrupting the active site and potentially hindering catalytic activity. Thermal denaturation stability assays using recombinant protein show the impact of D95N and I163T substitution on the protein stability.ConclusionsThese data show that KLK3 SNPs disrupt dynamic communication of the key loops required for proteolytic activity of PSA, which may explain the association of these SNPs with prostate cancer risk and/or progression. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
This work was supported by the Cancer Council Queensland and Prostate Cancer Foundation of Australia (PCFA) to JB. JC was supported by an NHMRC Principal Research Fellowship. JB was supported by NHMRC Career Development and Advance QLD MCR Research Fellowships and the Education and Research Committee (SERC) of Pathology Queensland. HK was supported by the Sigrid Juselius Foundation and Magnus Ehrnrooth Foundation.; https://hdl.handle.net/10138/627150; 001666716400001 |
| Availability: |
https://hdl.handle.net/10138/627150 |
| Rights: |
cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.2713BB1B |
| Database: |
BASE |