The Lysosomal Cysteine Proteases

McGrath, Mary E.

doi:10.1146/annurev.biophys.28.1.181

Cited by 295 publications

(259 citation statements)

References 103 publications

Supporting

Mentioning

247

Contrasting

Unclassified

Order By: Relevance

“…A description of some of the conserved features follows. Although the mature protein is a single polypeptide chain, it is folded into two globular domains, by convention referred to as the left (L, the N-terminal) and right (R, the C-terminal) domains [5]. Where the domains are apposed to each other, they form a cleft which is wider at one end than at the other and thus wedge shaped.…”

Section: Resultsmentioning

confidence: 99%

“…they are proteases) either at the ends of the target molecule, releasing the terminal amino acid residues (exopeptidases), or within the molecule, splitting it into peptides (endopeptidases). They are intracellular proteases whose activation requires an acidic environment such as that found in lysosomes [4][5][6]. Over 20 different cathepsins have been identified in mammals, 14 of them in humans, and designated by capital letters or in some cases by numerals.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phylogeny of Antigen‐Processing Enzymes: Cathepsins of a Cephalochordate, an Agnathan and a Bony Fish

et al. 2003

View full text Add to dashboard Cite

Cathepsins are enzymes that have been cleaving peptide bonds of lysosomal proteins probably since lysosomes appeared in early eucaryotes. When the adaptive system emerged in gnathostomes, cathepsins were recruited to produce peptides for loading onto the major histocompatibility complex class II molecules and for degrading the class II-associated invariant chain just before the loading. The circumstances under which this recruitment took place are unclear because the knowledge about vertebrate cathepsins is limited largely to mammals. To shed light on the recruitment, 10 amphioxus, one lamprey and one cichlid fish cathepsin cDNA clone were characterized and analysed phylogenetically. Disregarding cathepsin O, whose phylogenetic position is uncertain, the analysis confirms the existence of two old lines of descent, the B and the L lineages of cathepsins, which diverged from each other early in the evolution of eucaryotes. The B lineage encompasses cathepsins B, C and Z (X). The L lineage splits off sublineages encompassing cathepsins F and W before the plant-animal separation and cathepsin H early in the evolution of the metazoa. The remaining cathepsins belonging to the L lineage diverged from one another during the evolution of vertebrates: S, K and L before the emergence of bony fishes, and the group of rodent placentally expressed cathepsins [J (P), M, Q, R, 3, 6, 7 and 8] as well as the testis/ova-expressed cathepsins (testins) probably after the divergence of rodents from primates. The part possibly played by the adaptive immune system in some of these divergences is discussed.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phylogeny of Antigen‐Processing Enzymes: Cathepsins of a Cephalochordate, an Agnathan and a Bony Fish

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Cathepsins belong to the papain family, which are lysosomal cysteine proteases [1,2], and play the essential roles in a series of highly regulated life processes [3]. They involve in antigen processing and presentation, tumor progression and metastasis, bone resorbtion and osteolysis, a variety of parasitic infection [4e7], tissue invasion [8], food digestion and uptake [9], immune evasion [10] and molting [11].…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and characterization of cathepsin L from freshwater mussel, Cristaria plicata

et al. 2014

Fish & Shellfish Immunology

View full text Add to dashboard Cite

“…We chose to focus on the P2 position as this is the primary structural determinant of specificity for cathepsin B [17]. RAW264.7 lysates were pre-treated with the P2 fixed PSCL and residual cathepsin B active sites were detected by labeling with f-hex-VPED-AOMK (Supplemental Fig.…”

mentioning

confidence: 99%

Design of cell-permeable, fluorescent activity-based probes for the lysosomal cysteine protease asparaginyl endopeptidase (AEP)/legumain

Sexton

Witte

Blum

et al. 2007

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

Asparaginyl endopeptidase (AEP), also known as legumain, is a cysteine protease that has been ascribed roles in antigen presentation yet its exact role in human biology remains poorly understood. We report here the use of a positional scanning combinatorial library of peptide AOMKs containing a P1 aspartic acid to probe the P2, P3 and P4 subsite specificity of endogenous legumain. Using inhibitor specificity profiles of cathepsin B and legumain, we designed fluorescent ABPs that are highly selective, cell permeable reagents for monitoring legumain activity in complex proteomes.Asparaginyl Endopeptidase (AEP), or legumain, was originally identified in leguminous seeds as a cysteine protease with specificity for asparagine residues in the P1 position [1]. The mammalian legumain homologue is a lysosomal cysteine protease that is a member of the clan CD protease family which includes the caspases, separase and the gingipains [2]. Mammalian legumain has been ascribed a role in the initiation of invariant chain processing during MHC class II mediated antigen presentation [3,4]. Although the nature of this activity remains controversial, legumain is undoubtedly a key player in lysosomal proteolysis, contributing to the processing of antigenic peptides as well as the processing of the papain family cathepsins [5].Like all endocytic proteases, legumain is synthesized as an inactive zymogen, and its activity is regulated by post-translational activation events. Therefore, tools that can be used to monitor legumain's activity are necessary in order to understand its functional role. Activity based probes (ABPs) are reagents that can specifically label active proteases, thus allowing their activity, and more importantly their regulation, to be directly monitored [6,7]. Our laboratory recently reported a synthesis strategy based on the general solid phase methods developed by Ellman and co-workers [8] for the production of peptidyl acyloxymethyl ketone ABPs for diverse cysteine protease activities [9].We have previously demonstrated that the biotinylated ABP b-hex-D-AOMK efficiently labels endogenous legumain in 816 B cell lysates [9]. However this reagent lacks cell permeability and its overall selectivity towards legumain had not been extensively examined. We therefore Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Fig. 1a, b). Both ABPs potently labeled a ∼38 kDa protein in acidic proteomes from 816 B cells or RAW264.7 monocytes. This activity was confirmed to be legumain by immunoprecipitation using antisera specific for legumain. In addition to the ∼38 kDa predominant ...

show abstract

The Lysosomal Cysteine Proteases

Cited by 295 publications

References 103 publications

Phylogeny of Antigen‐Processing Enzymes: Cathepsins of a Cephalochordate, an Agnathan and a Bony Fish

Phylogeny of Antigen‐Processing Enzymes: Cathepsins of a Cephalochordate, an Agnathan and a Bony Fish

Molecular cloning and characterization of cathepsin L from freshwater mussel, Cristaria plicata

Design of cell-permeable, fluorescent activity-based probes for the lysosomal cysteine protease asparaginyl endopeptidase (AEP)/legumain

Contact Info

Product

Resources

About