The broadly expressed protein p62/SQSTM1 in Drosophila melanogaster adopts tissue-specific secondary and tertiary structural conformations that enable mutually exclusive functions—autophagy in midgut versus mitochondria-associated protein degradation in muscle—with these structural differences encoded by an intrinsically disordered region (IDR2) that acts as a molecular switch to determine tissue-specific domain interactions and binding partner preferences.

Protein structure dictate function, and proteins often perform the same function in different cell/tissue-type environments. Here, we report that in Drosophila melanogaster, the broadly expressed protein p62/SQSTM1 instead performs mutually exclusive functions across tissues – autophagy in midgut and mitochondria-associated proteostasis in muscle. These functional differences arise from tissue-specific secondary and tertiary structures adopted by the same p62 polypeptide, rather than protein abundance, isoforms, post-translational modification, or binding-partner availability. The tissue-specific structures are cell autonomous and resistant to environmental perturbation. Deletion of a short intrinsically disordered region converts muscle p62 to a midgut-like structural and functional state, but this forced switch causes muscle dysfunction, linking tissue-specific physiology to alternative structural states of the same polypeptide. We posit that Drosophila p62 exemplifies a mechanism for tissue-specificity in which intrinsic structural plasticity and the physiochemical/molecular environment of a tissue enable a broadly expressed protein to adopt tissue-specific structure and function.