Analysis of Protein Function in the Twilight Zone of Homology Detection.

The identification of both sequence and structural similarities among proteins represents a potent method for deducing functional and evolutionary connections within both known and unknown proteins. This approach can yield experimentally tractable hypotheses, contributing to an enhanced comprehension of protein functions.

Proteins containing BRICHOS domains have been implicated in an unusually broad spectrum of pathologies, including cancer, obesity, and two amyloid-like diseases. The BRICHOS domains themselves are characterized as intramolecular chaperones that actively prevent amyloid-like aggregation of the mature polypeptides within these proteins. By conducting a structural analysis that involves comparing AlphaFold models based on coevolution and considering sequence conservation, we have identified new members of this protein family in humans.