# TAU R406W Research Report **Protein:** TAU R406W **Variant:** R406W **UniProt ID:** P10636 **Disease Association:** Alzheimer's disease **Report Generated:** 2026-04-14 05:03 UTC **AlphaFold Confidence (pLDDT):** 55.0% **Structure Folded:** 2026-04-10 --- ## Structure Summary The R406W mutation in tau protein causes a rare inherited form of Alzheimer's disease with memory loss and brain degeneration. Structural prediction of this variant yielded low confidence (pLDDT 55.0), indicating this region of tau is highly flexible and disordered, which makes it difficult to predict stable structures. This disorder is biologically important, as tau's flexible tail region allows it to interact with many cellular partners and undergo disease-related modifications like phosphorylation. --- Tau R406W is a disease-causing mutation located in the C-terminal tail region of the tau protein, which naturally exists in an unstructured, disordered state. The AlphaFold2 structural prediction yielded an average confidence score of 55.0 pLDDT, well below the 70 threshold typically required for reliable structural interpretation. This low confidence reflects the inherent disorder of tau's C-terminus rather than a prediction failure—tau normally lacks a fixed three-dimensional structure in this region, allowing it to remain flexible and interact with diverse cellular partners. The R406W mutation causes autosomal dominant familial Alzheimer's disease with a distinct pattern of pathology. Unlike typical Alzheimer's disease, R406W carriers develop neurodegeneration with mixed 3R and 4R tau aggregates (tau isoforms with different numbers of microtubule-binding repeats) but typically without amyloid-beta plaques [1]. Studies have identified elevated phosphorylation of tau at position T217 in cerebrospinal fluid as a distinctive biomarker for R406W carriers, independent of amyloid pathology [1]. The mutation disrupts tau's normal interaction with the plasma membrane by abolishing binding to annexin A2, a protein that helps anchor tau to cell membranes, while microtubule binding remains intact. This leads to abnormal tau distribution within neurons, with reduced trapping at the tips of neuronal processes. Laboratory studies indicate R406W promotes tau aggregation into filaments that accumulate in neurons, though the molecular mechanism differs from other tau mutations. In transgenic mice, R406W tau forms hyperphosphorylated, congophilic inclusions (aggregates that bind Congo red dye, a marker of protein fibrils) in forebrain neurons, causing memory deficits. The mutation also triggers severe disruption of calcium signaling in neuronal nuclei, depleting the transcription factor CREB and accelerating age-related neurodegeneration in fruit fly models—effects that can be partially rescued by activating calcium-regulating BK channels. Given the very low structural confidence, specific atomic-level interpretations of how R406W alters tau structure cannot be made from this prediction. The biological effects of this mutation—membrane binding disruption, altered phosphorylation patterns, aggregation propensity, and calcium dysregulation—likely stem from changes in tau's dynamic ensemble of disordered conformations and protein-protein interactions rather than from alterations to a stable folded structure. Understanding R406W pathogenesis requires experimental techniques suited to studying disordered proteins, such as NMR spectroscopy or single-molecule fluorescence, rather than relying solely on structural prediction. ## Works Cited [1] Lin et al. (2026). Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer's Disease. medRxiv : the preprint server for health sciences. 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(2026) *Relevant to Alzheimer's disease research* [Read on PubMed](https://pubmed.ncbi.nlm.nih.gov/41619269/) --- ## Open Targets Disease Associations | Disease | Score | Data Sources | |---------|-------|--------------| | Pick disease | 0.760 | literature, animal_model, genetic_association, genetic_literature | | frontotemporal dementia | 0.736 | literature, genetic_association | | supranuclear palsy, progressive, 1 | 0.735 | literature, genetic_association, genetic_literature | | Atypical progressive supranuclear palsy | 0.723 | animal_model, genetic_association, genetic_literature | | Progressive supranuclear palsy - parkinsonism | 0.722 | literature, genetic_association, genetic_literature | | Classical progressive supranuclear palsy | 0.717 | literature, genetic_association, clinical, genetic_literature | | progressive supranuclear palsy | 0.708 | literature, genetic_association, genetic_literature, clinical | | progressive supranuclear palsy-parkinsonism syndrome | 0.655 | literature, genetic_association, genetic_literature | | semantic dementia | 0.651 | literature, animal_model, genetic_association, genetic_literature | | late-onset Parkinson disease | 0.632 | literature, genetic_association, genetic_literature | *...and 1172 more associations* --- *Generated by [Clarity Protocol](https://clarityprotocol.io)* **Data Sources:** - Structure predictions: AlphaFold via ColabFold - Clinical variant data: ClinVar, gnomAD - Disease associations: Open Targets Platform - Research findings: AI agents (PubMed, clinical databases)