The Type 4 Prepilin Peptidases Comprise a Novel Family of Aspartic Acid Proteases

LaPointe, Christian F.; Taylor, Ronald K.

doi:10.1074/jbc.275.2.1502

Cited by 177 publications

(156 citation statements)

References 36 publications

Supporting

Mentioning

149

Contrasting

Order By: Relevance

“…The conserved GD motif lies in TM7 of PS1. This motif is likewise found on the C-terminal side of the active site of bacterial TFPP, and mutation of the aspartate residue of the GD motif blocks its ability to remove leader peptides from certain substrates (LaPointe and Taylor, 2000). Although the primary sequences of PS and TFPP are not highly similar overall, the similar requirement for the aspartate-containing motifs for proteolysis from bacteria to humans suggests that TFPP and PS are novel polytopic membrane aspartyl proteases (Steiner et al, 2000).…”

Section: From Bacterial Proteases To Ps: a Conserved Active Site Motifmentioning

confidence: 97%

Intramembrane proteolysis by presenilin and presenilin-like proteases

Xia

Wolfe

2003

Journal of Cell Science

View full text Add to dashboard Cite

Regulated intramembrane proteolysis is a novel mechanism involving proteases that hydrolyze their substrates in a hydrophobic environment. Presenilin (PS) 1 and PS 2 are required for intramembrane cleavage of an increasing number of type I membrane proteins, including the amyloid precursor protein of Alzheimer's disease and the Notch receptor, which signals during differentiation and development. Mutagenesis, affinity labeling, biochemical isolation, and reconstitution in cells reveal that PS, in complex with co-factors nicastrin, APH-1 and PEN-2, apparently contains the active site ofγ-secretase, a novel membrane aspartyl protease. In addition, other related aspartyl proteases have been identified. These include members of the type-4 prepilin peptidase family in bacteria, which are known proteases and carry a GD motif conserved in PS. A group of multi-pass membrane proteins found in eukaryotes also contain YD and LGXGD motifs in two transmembrane domains that are conserved in PS and postulated to constitute an aspartyl protease active site. Among these is signal peptide peptidase (SPP), which cleaves remnant signal peptides derived from signal-peptidase-mediated ectodomain shedding. SPP cuts type II membrane proteins, illustrating that PS-like proteases play a key role in intramembrane proteolysis of single-pass membrane proteins oriented in either direction.

show abstract

Section: From Bacterial Proteases To Ps: a Conserved Active Site Motifmentioning

confidence: 97%

Intramembrane proteolysis by presenilin and presenilin-like proteases

Xia

Wolfe

2003

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Pre-pilin peptidases compose a unique class of bi-lobed aspartate proteases (LaPointe & Taylor, 2000). A third protein, the secretin, has been analysed in some detail in the P. aeruginosa type IV pilus system and also in EPEC.…”

Section: Introductionmentioning

confidence: 99%

BfpU, a soluble protein essential for type IV pilus biogenesis in enteropathogenic Escherichia coli

et al. 2002

View full text Add to dashboard Cite

A cluster of 14 genes located on the large plasmid of enteropathogenic Escherichia coli (EPEC) strains is sufficient to direct the biogenesis of the type IV bundle-forming pilus (BFP) in a recombinant E. coli host. The fifth gene in the cluster, bfpU, encodes a protein that is predicted to be localized to the periplasmic space. To determine whether BfpU is necessary for pilus biogenesis, the authors constructed a non-polar bfpU mutant EPEC strain by allelic exchange. The mutant strain was unable to perform localized adherence and auto-aggregation, two phenotypes associated with BFP expression, and it failed to make BFP. These phenotypes were restored to the bfpU mutant by a plasmid containing bfpU. There was no difference between the wild-type and bfpU mutant strains in their expression or processing of the pre-pilin protein or in their localization of the pilin protein in the inner and outer membranes. Fractionation studies revealed that BfpU is completely soluble and is detected in both the periplasm and the cytoplasm. Thus, BfpU represents a novel protein required for type IV pilus assembly.

show abstract

“…PSs are founding members of polytopic GxGD-type aspartyl proteases that include the type 4 prepilin peptidases (LaPointe and Taylor, 2000), signal peptide peptidase (SPP) (Weihofen et al, 2002), and its homologs (Krawitz et al, 2005). These protease families are characterized by a highly conserved GxGD sequence motif (Steiner et al, 2000), which includes the C-terminal active site aspartate.…”

Section: Introductionmentioning

confidence: 99%

The GxGD Motif of Presenilin Contributes to Catalytic Function and Substrate Identification of γ-Secretase

Yamasaki¹,

Eimer²,

Okochi³

et al. 2006

J. Neurosci.

View full text Add to dashboard Cite

␥-Secretase is a multisubunit aspartyl protease complex that catalyzes intramembrane cleavage of ␤-amyloid precursor protein (APP), a substrate key to Alzheimer's disease pathogenesis, and of Notch, a substrate crucial for cell differentiation. How ␥-secretase recognizes and selects substrates is currently barely understood. Recent data suggest that its subunit nicastrin serves as an initial substrate receptor, which might subsequently forward substrates to the active site domain located in its catalytic subunit presenilin (PS), where an additional substrate binding site has been proposed. We now used an active site domain swapping approach of PS1 with its most distant homolog, spermatogenesis defective (SPE-4), to identify sequence determinants in this region. Strikingly, when the active site domain of PS1 was exchanged with that of SPE-4, the chimeric protein, PS1/SPE-4 6/7 , supported APP but not Notch processing. In addition, PS1/SPE-4 6/7 was strongly impaired in Caenorhabditis elegans Notch signaling in vivo. Mapping experiments identified a single amino acid at position x of the GxGD motif, which contains one of the two active site aspartates, to be responsible for the observed defect in Notch processing and signaling. Our data thus implicate a role of the GxGD motif in catalytic function and substrate identification of ␥-secretase.

show abstract

The Type 4 Prepilin Peptidases Comprise a Novel Family of Aspartic Acid Proteases

Cited by 177 publications

References 36 publications

Intramembrane proteolysis by presenilin and presenilin-like proteases

Intramembrane proteolysis by presenilin and presenilin-like proteases

BfpU, a soluble protein essential for type IV pilus biogenesis in enteropathogenic Escherichia coli

The GxGD Motif of Presenilin Contributes to Catalytic Function and Substrate Identification of γ-Secretase

Contact Info

Product

Resources

About