ER aminopeptidases generate a unique pool of peptides for MHC class I molecules

Serwold, Thomas; Gaw, Stephanie L.; Shastri, Nilabh

doi:10.1038/89800

Cited by 173 publications

(107 citation statements)

References 51 publications

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“…Of the chelating agents tested, 1,10-phenanthroline effectively inhibited the enzyme activity, but EDTA had no effect up to 1 mM. It is noteworthy here that the inhibitor profile of L-RAP is consistent with those of putative ER resident aminopeptidases, which trim the MHC class I-presented antigenic precursor peptides (34).…”

Section: Fig 4 Subcellular Localization Of L-rapsupporting

confidence: 54%

“…L-RAP fulfills several criteria for the trimming enzyme of precursor peptides so far reported (34). 1) It is a metallopeptidase inhibited efficiently by 1,10-phenanthroline but not by EDTA.…”

Section: Discussionmentioning

confidence: 88%

“…It now well recognized that the precursors to MHC class-I-presented peptides with extra N-terminal residues are trimmed to mature epitopes in the ER, and A-LAP/ERAP1 is the first enzyme responsible for the processing in the ER (9,16). On the other hand, cytoplasmic enzymes such as PSA, lens leucine aminopeptidase, bleomycin hydrolase, and thimet oligopeptidase are thought to contribute to limit antigen presentation in vivo by destroying precursor peptides (34,(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

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Human Leukocyte-derived Arginine Aminopeptidase

Tanioka

Hattori

Masuda

et al. 2003

Journal of Biological Chemistry

178

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In this study we report the cloning and characterization of a novel human aminopeptidase, which we designate leukocyte-derived arginine aminopeptidase (L-RAP). The sequence encodes a 960-amino acid protein with significant homology to placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase. The predicted L-RAP contains the HEXXH(X) 18 E zinc-binding motif, which is characteristic of the M1 family of zinc metallopeptidases. Phylogenetic analysis indicates that L-RAP forms a distinct subfamily with placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in the M1 family. Immunocytochemical analysis indicates that L-RAP is located in the lumenal side of the endoplasmic reticulum. Among various synthetic substrates tested, L-RAP revealed a preference for arginine, establishing that the enzyme is a novel arginine aminopeptidase with restricted substrate specificity. In addition to natural hormones such as angiotensin III and kallidin, L-RAP cleaved various N-terminal extended precursors to major histocompatibility complex class I-presented antigenic peptides. Like other proteins involved in antigen presentation, L-RAP is induced by interferon-␥. These results indicate that L-RAP is a novel aminopeptidase that can trim the N-terminal extended precursors to antigenic peptides in the endoplasmic reticulum.

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Section: Fig 4 Subcellular Localization Of L-rapsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Human Leukocyte-derived Arginine Aminopeptidase

Tanioka

Hattori

Masuda

et al. 2003

Journal of Biological Chemistry

178

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“…Specifically, a crucial protease should be an uncharacterized metallopeptidase that operates in a sequential pathway with the proteasomes to process ENV (28). In the endoplasmic reticulum, a metallo-aminopeptidase has been described that leads to the accumulation of peptides with P at position 2 (52). This aminopeptidase could be responsible for the production of G9I, and a potential accumulation of this peptide would result in its over-representation in the pool of natural peptides, despite the lower stability of the D d /G9I complexes.…”

Section: Discussionmentioning

confidence: 99%

An Endogenous HIV Envelope-derived Peptide without the Terminal NH3+ Group Anchor Is Physiologically Presented by Major Histocompatibility Complex Class I Molecules

Samino

López

Guil

et al. 2004

Journal of Biological Chemistry

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“…It had been originally proposed that peptide precursors in the ER bind to class I molecules weakly and that the loose ends are then trimmed by exopeptidases until the tight-binding eight-or nineresidue epitopes are generated (29). However, a remarkable feature of ERAP1 is that, in the absence of any MHC class I molecules to serve as a template, it trims antigenic precursors but seems to lose activity when eight-or nine-residue epitopes are generated (27).…”

mentioning

confidence: 99%

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

Chang

Momburg

Bhutani

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

300

336

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Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an IFN-␥-induced aminopeptidase in the endoplasmic reticulum that trims longer precursors to the antigenic peptides presented on MHC class I molecules. We recently reported that purified ERAP1 trimmed N-extended precursors but spared peptides of 8 -9 residues, the length required for binding to MHC class I molecules. Here, we show another remarkable property of ERAP1: that it strongly prefers substrates 9 -16 residues long, the lengths of peptides transported efficiently into the ER by the transporter associated with antigen processing (TAP) transporter. This aminopeptidase rapidly degraded a model 13-mer to a 9-mer and then stopped, even though the substrate and the product had identical N-and C-terminal sequences. No other aminopeptidase, including the closely related ER-aminopeptidase ERAP2, showed a similar length preference. Unlike other aminopeptidases, the activity of ERAP1 depended on the C-terminal residue of the substrate. ERAP1, like most MHC class I molecules, prefers peptides with hydrophobic C termini and shows low affinity for peptides with charged C termini. Thus, ERAP1 is specialized to process precursors transported by TAP to peptides that can serve as MHC class I epitopes. Its ''molecular ruler'' mechanism involves binding the hydrophobic C terminus of the substrate 9 -16 residues away from the active site.antigen presentation ͉ antigen processing ͉ proteases M HC class I molecules bind tightly and display on the cell surface antigenic peptides that are derived from peptides generated during the degradation of intracellular proteins. If nonnative peptides (e.g., from viral proteins) are presented, they are recognized by circulating cytotoxic T lymphocytes (1-4). To fit in the groove in most MHC class I molecules, these antigenic peptides must have a length of 8-10 residues (5, 6), although certain class I molecules can admit peptides up to 11 residues (7). It is now firmly established that the proteasome pathway is responsible for the generation of the great majority of antigenic peptides (8-10). Proteasomes generally degrade proteins to peptide fragments ranging from 2-25 residues long (11), but most are too short (Ͻ8 residues) for antigen presentation. Several studies using proteasome inhibitors have further shown that cleavages within proteasomes define the C-terminal residues of MHC class I-presented peptides (12). However, their N termini often are generated by aminopeptidases, which trim longer N-extended proteasome products to the mature epitopes (13). In fact, proteasomes, and especially immunoproteasomes (1), the forms found in immune tissues and induced by IFN-␥ elsewhere, seem to preferentially generate such longer precursors (14), whose presentation requires Nterminal processing. Several cytosolic peptidases, including tripeptidyl peptidase II (TPPII) (15), bleomycin hydrolase and puromycin-sensitive aminopeptidase (16), and the IFN-␥-inducible enzyme leucine aminopeptidase (17), may play a role in trimming some precursors to antige...

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ER aminopeptidases generate a unique pool of peptides for MHC class I molecules

Cited by 173 publications

References 51 publications

Human Leukocyte-derived Arginine Aminopeptidase

Human Leukocyte-derived Arginine Aminopeptidase

An Endogenous HIV Envelope-derived Peptide without the Terminal NH3+ Group Anchor Is Physiologically Presented by Major Histocompatibility Complex Class I Molecules

The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism

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