Structure and function of SPP/SPPL proteases: insights from biochemical evidence and predictive modeling

More than 20 years ago, signal peptide peptidase (SPP) and its homologues, the signal peptide peptidase‐like (SPPL) proteases have been identified based on their sequence similarity to presenilins, a related family of intramembrane aspartyl proteases. Other than those for the presenilins, no high‐resolution structures for the SPP/SPPL proteases are available. Despite this limitation, over the years bioinformatical and biochemical data have accumulated, which altogether have provided a picture of the overall structure and topology of these proteases, their localization in the cell, the process of substrate recognition, their cleavage mechanism, and their function. Recently, the artificial intelligence‐based structure prediction tool AlphaFold has added high‐confidence models of the expected fold of SPP/SPPL proteases. In this review, we summarize known structural aspects of the SPP/SPPL family as well as their substrates. Of particular interest are the emerging substrate recognition and catalytic mechanisms that might lead to the prediction and identification of more potential substrates and deeper insight into physiological and pathophysiological roles of proteolysis. Signal peptide peptidase (SPP) and signal peptide peptidase‐like (SPPL) proteases are intramembrane aspartyl proteases involved in various cellular functions. Despite lacking high‐resolution structures, bioinformatic and biochemical data have shed light on their structure, localization, substrate recognition, cleavage mechanism, and function. Recently, the artificial intelligence‐based tool AlphaFold has provided high‐confidence models for SPP/SPPL proteases. This review summarizes structural aspects and substrates of these proteases, focusing on substrate recognition and catalytic mechanisms.