HRD1
S. cerevisiae
E3 ubiquitin-protein ligase HRD1
What the model saw
Gene: HRD1 Organism: Saccharomyces cerevisiae Known functions: E3 ubiquitin-protein ligase HRD1. identical protein binding. protein binding. ubiquitin protein ligase activity. ubiquitin-protein transferase activity. zinc ion binding.
View unredacted entry
E3 ubiquitin-protein ligase HRD1. identical protein binding. protein binding. ubiquitin protein ligase activity. ubiquitin-protein transferase activity. zinc ion binding.
Solver output
HRD1 encodes the central E3 ubiquitin-protein ligase of the ER-associated degradation (ERAD) pathway in S. cerevisiae. Its ubiquitin-protein transferase activity targets misfolded or aberrant ER-lumenal and transmembrane proteins for ubiquitination and subsequent proteasomal degradation, thereby maintaining ER proteostasis. Loss of ERAD function leads to accumulation of misfolded proteins, chronic ER stress, and activation of the unfolded protein response (UPR), all of which are associated with accelerated aging and shortened lifespan. By clearing aberrant proteins and limiting proteotoxic stress, HRD1 activity directly supports proteostasis, a key determinant of longevity. Its zinc ion binding is consistent with the RING-domain architecture required for E3 ligase catalytic activity in this pathway.
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 but the ground truth is anti_longevity. The model's reasoning about HRD1's role in ERAD and proteostasis is mechanistically plausible in general terms, but it led to the wrong conclusion. HRD1 is actually anti-longevity in yeast, meaning its deletion or loss extends lifespan rather than shortening it. The model assumed that because HRD1 maintains proteostasis, it must be pro-longevity, but the actual experimental data shows the opposite - HRD1 deletion extends lifespan in S. cerevisiae. The model's confidence of 0.72 is relatively high for an incorrect answer. The mechanistic reasoning, while coherent, is ultimately wrong because it failed to account for the possibility that ERAD activity via HRD1 might actually limit longevity (perhaps by degrading proteins that would otherwise promote longevity, or through other mechanisms). The reasoning quality is moderate - it's internally consistent but reaches the wrong conclusion.
Raw API responses
solver
{
"reasoning": "HRD1 encodes the central E3 ubiquitin-protein ligase of the ER-associated degradation (ERAD) pathway in S. cerevisiae. Its ubiquitin-protein transferase activity targets misfolded or aberrant ER-lumenal and transmembrane proteins for ubiquitination and subsequent proteasomal degradation, thereby maintaining ER proteostasis. Loss of ERAD function leads to accumulation of misfolded proteins, chronic ER stress, and activation of the unfolded protein response (UPR), all of which are associated with accelerated aging and shortened lifespan. By clearing aberrant proteins and limiting proteotoxic stress, HRD1 activity directly supports proteostasis, a key determinant of longevity. Its zinc ion binding is consistent with the RING-domain architecture required for E3 ligase catalytic activity in this pathway.",
"confidence": 0.72,
"key_pathways": [
"ER-associated degradation (ERAD)",
"ubiquitin-proteasome system (UPS)",
"unfolded protein response (UPR)"
],
"mechanism_class": "loss_of_proteostasis",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning about HRD1's role in ERAD and proteostasis is mechanistically plausible in general terms, but it led to the wrong conclusion. HRD1 is actually anti-longevity in yeast, meaning its deletion or loss extends lifespan rather than shortening it. The model assumed that because HRD1 maintains proteostasis, it must be pro-longevity, but the actual experimental data shows the opposite - HRD1 deletion extends lifespan in S. cerevisiae. The model's confidence of 0.72 is relatively high for an incorrect answer. The mechanistic reasoning, while coherent, is ultimately wrong because it failed to account for the possibility that ERAD activity via HRD1 might actually limit longevity (perhaps by degrading proteins that would otherwise promote longevity, or through other mechanisms). The reasoning quality is moderate - it's internally consistent but reaches the wrong conclusion.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}