DER1
S. cerevisiae
derlin
What the model saw
Gene: DER1 Organism: Saccharomyces cerevisiae Known functions: derlin. misfolded protein binding. protein binding. signal recognition particle binding.
View unredacted entry
derlin. misfolded protein binding. protein binding. signal recognition particle binding.
Solver output
DER1 encodes a derlin family protein in S. cerevisiae, which is a core component of the ER-associated degradation (ERAD) machinery. Its ability to bind misfolded proteins and interact with the signal recognition particle positions it as a key factor in recognizing and retrotranslocating aberrant ER-lumenal and membrane proteins for proteasomal degradation. By facilitating the clearance of misfolded proteins from the ER, DER1 directly supports proteostasis — the maintenance of which is a hallmark of longevity. Loss of ERAD components leads to accumulation of misfolded proteins, ER stress, and activation of the unfolded protein response (UPR), all of which are associated with accelerated aging. Thus, the normal function of DER1 in promoting proteostatic quality control is expected to be pro-longevity.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model predicted pro_longevity with 0.72 confidence, but the ground truth is anti_longevity. The model's reasoning about DER1's role in ERAD and proteostasis is mechanistically plausible in general terms, but it led to the wrong conclusion. In yeast, DER1 deletion (loss of function) actually extends lifespan, making it anti_longevity (i.e., its normal function shortens lifespan). The model assumed that because ERAD supports proteostasis, DER1 must be pro-longevity, but this is incorrect — the actual experimental data shows the opposite. The model's reasoning is coherent but based on an incorrect assumption about the direction of effect. This is a case where the general mechanistic framework (ERAD = good for proteostasis = pro-longevity) was applied without accounting for the actual experimental evidence in yeast showing that DER1 deletion extends lifespan.
Raw API responses
solver
{
"reasoning": "DER1 encodes a derlin family protein in S. cerevisiae, which is a core component of the ER-associated degradation (ERAD) machinery. Its ability to bind misfolded proteins and interact with the signal recognition particle positions it as a key factor in recognizing and retrotranslocating aberrant ER-lumenal and membrane proteins for proteasomal degradation. By facilitating the clearance of misfolded proteins from the ER, DER1 directly supports proteostasis — the maintenance of which is a hallmark of longevity. Loss of ERAD components leads to accumulation of misfolded proteins, ER stress, and activation of the unfolded protein response (UPR), all of which are associated with accelerated aging. Thus, the normal function of DER1 in promoting proteostatic quality control is expected to be pro-longevity.",
"confidence": 0.72,
"key_pathways": [
"ER-associated degradation (ERAD)",
"unfolded protein response (UPR)",
"proteasomal protein quality control"
],
"mechanism_class": "loss_of_proteostasis",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity with 0.72 confidence, but the ground truth is anti_longevity. The model's reasoning about DER1's role in ERAD and proteostasis is mechanistically plausible in general terms, but it led to the wrong conclusion. In yeast, DER1 deletion (loss of function) actually extends lifespan, making it anti_longevity (i.e., its normal function shortens lifespan). The model assumed that because ERAD supports proteostasis, DER1 must be pro-longevity, but this is incorrect — the actual experimental data shows the opposite. The model's reasoning is coherent but based on an incorrect assumption about the direction of effect. This is a case where the general mechanistic framework (ERAD = good for proteostasis = pro-longevity) was applied without accounting for the actual experimental evidence in yeast showing that DER1 deletion extends lifespan.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}