Signal peptide peptidases: a family of intramembrane-cleaving proteases that cleave type 2 transmembrane proteins.
Five genes encode the five human signal peptide peptidases (SPPs), which are intramembrane-cleaving aspartyl proteases (aspartyl I-CLiPs). SPPs have been conserved through evolution with family members found in higher eukaryotes, fungi, protozoa, arachea, and plants. SPPs are related to the presenilin family of aspartyl I-CLiPs but differ in several key aspects. Presenilins (PSENs) and SPPs both cleave the transmembrane region of membrane proteins; however, PSENs cleave type 1 membrane proteins whereas SPPs cleave type 2 membrane proteins. Though the overall homology between SPPs and PSENs is minimal, they are multipass membrane proteins that contain two conserved active site motifs YD and GxGD in adjacent membrane-spanning domains and a conserved PAL motif of unknown function near their COOH-termini. They differ in that the active site YD and GxGD containing transmembrane domains of SPPs are inverted relative to PSENs, thus, orienting the active site in a consistent topology relative to the substrate. At least two of the human SPPs (SPP and SPPL3) appear to function without additional cofactors, but PSENs function as a protease, called gamma-secretase, only when complexed with Nicastrin, APH-1 and Pen-2. The biological roles of SPP are largely unknown, and only a few endogenous substrates for SPPs have been identified. Nevertheless there is emerging evidence that SPP family members are highly druggable and may regulate both essential physiologic and pathophysiologic processes. Further study of the SPP family is needed in order to understand their biological roles and their potential as therapeutic targets.
Department of Neuroscience, Mayo Clinic, College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, United States. tgolde@mayo.edu
Todd E
TE
Golde
Michael S
MS
Wolfe
Doron C
DC
Greenbaum
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000145:classification* / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D010802:Phylogeny; D044464:Receptor, PAR-2 / Q000378:metabolism*
D044464:Receptor, PAR-2; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase