Unstable proteins are prone to form non-native interactions with other proteins and thereby may become toxic. To mitigate this, destabilized proteins are targeted by the protein quality control network. Here we present systematic studies of the cytosolic aspartoacylase, ASPA, where variants are linked to Canavan disease, a lethal neurological disorder. We determine the abundance of 6152 of the 6260 ( ~ 98%) possible single amino acid substitutions and nonsense ASPA variants in human cells. Most low abundance variants are degraded through the ubiquitin-proteasome pathway and become toxic upon prolonged expression. The data correlates with predicted changes in thermodynamic stability, evolutionary conservation, and separate disease-linked variants from benign variants. Mapping of degradation signals (degrons) shows that these are often buried and the C-terminal region functions as a degron. The data can be used to interpret Canavan disease variants and provide insight into the relationship between protein stability, degradation and cell fitness.

不稳定的蛋白质容易与其他蛋白质形成非天然相互作用，从而可能变得有毒。为了缓解这种情况，蛋白质质量控​​制网络将不稳定的蛋白质作为目标。在这里，我们提出了对胞浆天冬氨酸酰基酶 ASPA 的系统研究，其中的变异与卡纳万病（一种致命的神经系统疾病）有关。我们确定了人类细胞中 6260 个（约 98%）可能的单一氨基酸取代和无义 ASPA 变体中的 6152 个的丰度。大多数低丰度变体通过泛素-蛋白酶体途径降解，并在长时间表达后变得有毒。这些数据与热力学稳定性、进化保守性以及将疾病相关变异与良性变异分开的预测变化相关。降解信号（降解决定子）的图谱表明，这些信号通常被掩埋，并且 C 末端区域充当降解决定子。这些数据可用于解释卡纳万病变异，并深入了解蛋白质稳定性、降解和细胞适应性之间的关系。