Journal article
Molecular Modeling and In Vitro Functional Analysis of the RGS12 PDZ Domain Variant Associated with High-Penetrance Familial Bipolar Disorder
International journal of molecular sciences, Vol.25(21), 11431
10/24/2024
DOI: 10.3390/ijms252111431
PMCID: PMC11546610
PMID: 39518985
Abstract
Bipolar disorder’s etiology involves genetics, environmental factors, and gene–environment interactions, underlying its heterogeneous nature and treatment complexity. In 2020, Forstner and colleagues catalogued 378 sequence variants co-segregating with familial bipolar disorder. A notable candidate was an R59Q missense mutation in the PDZ (PSD-95/Dlg1/ZO-1) domain of RGS12. We previously demonstrated that RGS12 loss removes negative regulation on the kappa opioid receptor, disrupting basal ganglia dopamine homeostasis and dampening responses to dopamine-eliciting psychostimulants. Here, we investigated the R59Q variation in the context of potential PDZ domain functional alterations. We first validated a new target for the wildtype RGS12 PDZ domain—the SAPAP3 C-terminus—by molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation. While initial molecular dynamics (MD) studies predicted negligible effects of the R59Q variation on ligand binding, SPR showed a significant reduction in binding affinity for the three peptide targets tested. AlphaFold2-generated models predicted a modest reduction in protein–peptide interactions, which is consistent with the reduced binding affinity observed by SPR, suggesting that the substituted glutamine side chain may weaken the affinity of RGS12 for its in vivo binding targets, likely through allosteric changes. This difference may adversely affect the CNS signaling related to dynorphin and dopamine in individuals with this R59Q variation, potentially impacting bipolar disorder pathophysiology.
Details
- Title: Subtitle
- Molecular Modeling and In Vitro Functional Analysis of the RGS12 PDZ Domain Variant Associated with High-Penetrance Familial Bipolar Disorder
- Creators
- Percy S. Agogo-Mawuli - University of North TexasJoseph Mendez - University of North Texas Health Science CenterEmily A. Oestreich - Pacific Northwest University of Health SciencesDustin E. Bosch - University of IowaDavid P. Siderovski - University of North Texas
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.25(21), 11431
- DOI
- 10.3390/ijms252111431
- PMID
- 39518985
- PMCID
- PMC11546610
- NLM abbreviation
- Int J Mol Sci
- ISSN
- 1422-0067
- eISSN
- 1422-0067
- Publisher
- MDPI
- Grant note
- National Institutes of HealthUNTHSC Division of Research and Innovation (DRI)
The studies were supported by National Institutes of Health grants R01 DA048153 (to D.P.S.) and K08 AI159619 (to D.E.B.). P.S.A.-M. was supported by an internal seed grant from the UNTHSC Division of Research and Innovation (DRI).
- Language
- English
- Date published
- 10/24/2024
- Academic Unit
- Pathology
- Record Identifier
- 9984740855302771
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