PPP2R1A Research Notes

Gene Identity

• Gene: PPP2R1A (HGNC:9302)
• UniProt: P30153
• Protein: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PR65-alpha, PP2A-Aalpha)
• Family: Phosphatase 2A regulatory subunit A family

Core Function Summary

PPP2R1A encodes the major scaffolding (A-alpha) subunit of protein phosphatase 2A (PP2A). The protein contains 15 tandem HEAT repeats forming an elongated horseshoe-shaped structure PMID:9989501.

The primary molecular function is scaffolding: the C-terminal HEAT repeats (11-15) bind the catalytic C subunit (PPP2CA/PPP2CB), while the N-terminal repeats (1-10) bind regulatory B subunits PMID:17055435. This generates the PP2A holoenzyme heterotrimer.

PPP2R1A is NOT the catalytic phosphatase -- PPP2CA/PPP2CB perform the actual dephosphorylation. PPP2R1A is the structural scaffold that assembles the holoenzyme.

Key Complexes

1. PP2A core dimer: PPP2R1A + PPP2CA/PPP2CB (AC dimer) PMID:17055435
2. PP2A holoenzyme trimer: PPP2R1A + C subunit + one of many B subunits (B55/B56/PR72/striatin families) PMID:17174897
3. INTAC complex: Integrator + PP2A-AC, a noncanonical PP2A holoenzyme for transcription regulation PMID:33243860
4. STRIPAK complex: PP2AA-C + striatins + STRIP1/2 + MOB4, a noncanonical PP2A complex for Hippo signaling PMID:33633399
5. FAR/SIN/STRIPAK complex: Same as STRIPAK in yeast/metazoan nomenclature PMID:18782753

Subcellular Localization

• Cytoplasm/Cytosol: Primary location, by similarity and supported by multiple studies
• Nucleus: Experimental evidence via INTAC complex and CRTC3 studies [PMID:33243860, PMID:34004147, PMID:30611118]
• Chromatin: As part of INTAC complex for transcription regulation [PMID:33243860, PMID:34004147]
• Centromere: During mitosis, for Sgo1 localization and chromosome segregation PMID:16580887
• Lateral plasma membrane: In neurons, colocalizes with Galpha12 PMID:15525651
• Dendrites/neuronal cell body: In neurons PMID:15525651

Biological Processes

1. Transcription initiation surveillance / premature transcription termination: As part of INTAC complex [PMID:33243860, PMID:34004147, PMID:38570683]
2. snRNA processing: Integrator complex role PMID:16239144
3. Chromosome segregation: Centromeric PP2A protects cohesion PMID:16580887
4. Hippo signaling regulation: As STRIPAK component, negatively regulates Hippo pathway PMID:33633399
5. Cell signaling: General PP2A-mediated dephosphorylation of signaling proteins (AKT, ERK, etc.)

Disease Associations

• Cancer: Somatic mutations in endometrial/uterine serous carcinoma (up to 43% frequency), breast cancer, gliomas
• Houge-Janssens syndrome 2 (MIM:616362): Neurodevelopmental disorder with intellectual disability PMID:37761890

Key Literature References

• PMID:9989501 - Crystal structure of PR65/A subunit, 15 HEAT repeats
• PMID:17055435 - Crystal structure of PP2A core enzyme
• PMID:17174897 - Crystal structure of PP2A holoenzyme with B56
• PMID:33243860 - Discovery of INTAC complex
• PMID:34004147 - PP2A-Integrator-CDK9 axis in transcription
• PMID:33633399 - Cryo-EM of STRIPAK complex
• PMID:16580887 - PP2A at centromeres for chromosome segregation
• PMID:9847399 - Binding specificity of A subunit for B subunits and T antigens
• PMID:38123684 - Cryo-EM of PP2A:B55 complexes
• PMID:38570683 - INTAC in RNA Pol II termination