Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases

• SPP and SPPL are intramembrane-cleaving proteases of the GxGD type.
• SPP/SPPLs are conserved among eukaryotic species and have evolved distinct functions.
• In humans, SPP and SPPLs are involved in diverse physiological processes.
• SPP/SPPLs cleave type II membrane proteins within their transmembrane domain.
• SPP/SPPLs cleave the transmembrane domain of their substrates in a sequential manner.

Signal peptide peptidase (SPP) and the homologous SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 belong to the family of GxGD intramembrane proteases. SPP/SPPLs selectively cleave transmembrane domains in type II orientation and do not require additional co-factors for proteolytic activity. Orthologues of SPP and SPPLs have been identified in other vertebrates, plants, and eukaryotes. In line with their diverse subcellular localisations ranging from the ER (SPP, SPPL2c), the Golgi (SPPL3), the plasma membrane (SPPL2b) to lysosomes/late endosomes (SPPL2a), the different members of the SPP/SPPL family seem to exhibit distinct functions. Here, we review the substrates of these proteases identified to date as well as the current state of knowledge about the physiological implications of these proteolytic events as deduced from in vivo studies. Furthermore, the present knowledge on the structure of intramembrane proteases of the SPP/SPPL family, their cleavage mechanism and their substrate requirements are summarised. This article is part of a Special Issue entitled: Intramembrane Proteases.

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