Structural domains comprising this superfamily share the structure of an N-terminal pleckstrin homology (PH)-like domain of some ubiquitin carboxyl-terminal hydrolasesincluding USP26, USP29 and USP37. USP37 antagonizes the anaphase-promoting complex (APC/C) during G1/S transition by mediating deubiquitination of cyclin-A, process which promotes S phase entry PMID:21596315. USP26 is a regulator of androgen receptor (AR) signaling PMID:20501646. Both USP26 and USP37 play a major role for double-strand breaks repair by homologous recombination PMID:26101254. USP29 on the other hand is involved in apoptosis and oxidative stress PMID:21285945.

PH domains have diverse functions, although generally they are involved in targeting proteins to the correct cellular location or in the interaction with a binding partner PMID:22728242. Although they show little sequence conservation they all have a an electrostatically polarized common fold.