Evolutionary turnover of protein structural disorder drives aberrant proteome remodelling in naked mole rat

The naked mole rat is an evolutionary outlier among mammals, exhibiting extreme longevity, cancer resistance, hypoxia tolerance, pain insensitivity, eusociality, poikilothermy and other distinctive physiological traits, most of which likely resulted from its adaptation to highly adverse subterranean habitat. Despite accumulating data, the genetic and molecular basis underlying these traits remain poorly understood. Through analyses of 18 distinct protein attributes and allied datasets across hystricomorphs, myomorphs, carnivores, and primates, we observed lineage-specific evolutionary divergence in intrinsic protein disorder in the naked mole rat. The disorder turnover exhibited functional dichotomy. The gain of disorder preferentially associated with proteostasis(definition), immune regulation, neurodevelopment, skeletal growth and tumour suppressive properties, while loss of disorder modulated mostly the cardiac development. The proteins that gained disorder in NMR exhibited lower degradation rates, consistent with stabilization through phase-separation, while the proteins losing disorder show pronounced divergence in gene expression. The disorder turnover was primarily driven by indels affecting functional regions including Pfam domains, ANCHOR-predicted binding sites, short linear motifs, stress induced modifications of Tyr, Met, and Cys residues. Notably, the gained disordered regions were inferred to be redox-sensitive, aligning to exceptional stress tolerance in naked mole rats. Collectively, our results highlight an unusual and previously overlooked large-scale proteome remodelling that drives the molecular evolution of extraordinary traits of naked mole rat. <h4>Graphical abstract</h4>