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PolyQ length co-evolution in neural proteins.

ABSTRACT: Intermolecular co-evolution optimizes physiological performance in functionally related proteins, ultimately increasing molecular co-adaptation and evolutionary fitness. Polyglutamine (polyQ) repeats, which are over-represented in nervous system-related proteins, are increasingly recognized as length-dependent regulators of protein function and interactions, and their length variation contributes to intraspecific phenotypic variability and interspecific divergence. However, it is unclear whether polyQ repeat lengths evolve independently in each protein or rather co-evolve across functionally related protein pairs and networks, as in an integrated regulatory system. To address this issue, we investigated here the length evolution and co-evolution of polyQ repeats in clusters of functionally related and physically interacting neural proteins in Primates. We observed function-/disease-related polyQ repeat enrichment and evolutionary hypervariability in specific neural protein clusters, particularly in the neurocognitive and neuropsychiatric domains. Notably, these analyses detected extensive patterns of intermolecular polyQ length co-evolution in pairs and clusters of functionally related, physically interacting proteins. Moreover, they revealed both direct and inverse polyQ length co-variation in protein pairs, together with complex patterns of coordinated repeat variation in entire polyQ protein sets. These findings uncover a whole system of co-evolving polyQ repeats in neural proteins with direct implications for understanding polyQ-dependent phenotypic variability, neurocognitive evolution and neuropsychiatric disease pathogenesis.

SUBMITTER: Vaglietti S

PROVIDER: S-EPMC8121095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Nine neurodegenerative disorders, called polyglutamine (polyQ) diseases, are characterized by the formation of intranuclear amyloid-like aggregates by nine proteins containing a polyQ tract above a threshold length. These insoluble aggregates and/or some of their soluble precursors are thought to play a role in the pathogenesis. The mechanism by which polyQ expansions trigger the aggregation of the relevant proteins remains, however, unclear. In this work, polyQ tracts of different lengths were inserted into a solvent-exposed loop of the ?-lactamase BlaP and the effects of these insertions on the properties of BlaP were investigated by a range of biophysical techniques. The insertion of up to 79 glutamines does not modify the structure of BlaP; it does, however, significantly destabilize the enzyme. The extent of destabilization is largely independent of the polyQ length, allowing us to study independently the effects intrinsic to the polyQ length and those related to the structural integrity of BlaP on the aggregating properties of the chimeras. Only chimeras with 55Q and 79Q readily form amyloid-like fibrils; therefore, similarly to the proteins associated with diseases, there is a threshold number of glutamines above which the chimeras aggregate into amyloid-like fibrils. Most importantly, the chimera containing 79Q forms amyloid-like fibrils at the same rate whether BlaP is folded or not, whereas the 55Q chimera aggregates into amyloid-like fibrils only if BlaP is unfolded. The threshold value for amyloid-like fibril formation depends, therefore, on the structural integrity of the ?-lactamase moiety and thus on the steric and/or conformational constraints applied to the polyQ tract. These constraints have, however, no significant effect on the propensity of the 79Q tract to trigger fibril formation. These results suggest that the influence of the protein context on the aggregating properties of polyQ disease-associated proteins could be negligible when the latter contain particularly long polyQ tracts.

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PolyQ length co-evolution in neural proteins.

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