A New Role for Zn(II) Aminopeptidases: Antigenic Peptide Generation and Destruction

Abstract

During the last few years a novel role for previously known Zn(II) aminopeptidases has emerged, attracting a great deal of scientific interest to these molecules. Aminopeptidases appear now to play a key role in the last, yet crucial, proteolytic steps that generate small peptides for presentation onto MHC class I molecules so that the mature MHC-peptide complexes can be recognized by cytotoxic T-lymphocytes. In that context, ER aminopeptidases have been shown to strongly affect the adaptive immune response. ER aminopeptidase 1 (ERAP1) has been demonstrated to be a critical determinant of the immune response by generating mature antigenic epitopes from peptide precursors that arrive into the ER originating primarily from intracellular proteins degraded by the proteasome. At least one more related aminopeptidase, renamed ERAP2, appears to have important yet distinct roles in antigenic peptide generation. This review discusses recent findings that help to unravel the role of ER aminopeptidases in the immune response as well as the molecular properties that underlie this role. Determining the exact role and mechanism of action of these aminopeptidases will potentially provide tools for the pharmaceutical manipulation of the immune response on a subtle and qualitative level leading to novel therapeutic opportunities for the treatments of diseases ranging from autoimmunity to cancer.

A Naturally Variable Residue in the S1 Subsite of M1 Family Aminopeptidases Modulates Catalytic Properties and Promotes Functional Specialization

“…The primary role of both ERAP1 and 2 is to trim proteasome-generated peptides in the endoplasmic reticulum for loading onto class 1 MHC molecules (3,4). The specificity of the S1 subsite of ERAP1 is relatively broad, accepting a wide range of acidic, basic, and nonpolar P1 side chains (30,31).…”

“…For example, the mammalian ectoenzyme aminopeptidase N contributes to the metabolism of a number peptide hormones and has been implicated in a wide variety of physiological processes including blood pressure regulation, angiogenesis, and tumor metastasis (2). The endoplasmic reticulum aminopeptidases (ERAP) 3 1 and 2 trim peptides that are destined for major histocompatibility complex (MHC) class I presentation (3). These enzymes have been associated with ankylosing spondylitis, preeclampsia, and cervical cancer (4).…”

Crystal Structures of ERAP2 Complexed with Inhibitors Reveal Pharmacophore Requirements for Optimizing Inhibitor Potency

“…KEYWORDS: Aminopeptidase, inhibitors, X-ray crystallography, antigen E ndoplasmic reticulum aminopeptidase 2 (ERAP2) is an intracellular enzyme that belongs to the M1 family of zinc aminopeptidases and is tasked with processing antigenic peptide precursors to generate (antigenic) peptides for presentation by Major Histocompatibility Class I molecules. 1 With this function, ERAP2 can regulate adaptive immune responses in humans and influence cytotoxic responses against healthy or aberrant cells. ERAP2 has distinct specificity to the homologous ERAP1 and has been proposed to assist the trimming function of ERAP1 possibly through the formation of a functional dimer.…”

Novel selective inhibitors of aminopeptidases that generate antigenic peptides

“…[1][2][3][4] Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1/2), as well as Insulin regulated aminopeptidase (IRAP) can generate key antigenic peptides that help the human body fight pathogens and cancer but at the same time they can also destroy several antigenic peptides by over-trimming. [5][6][7] Both functions can contribute to human disease by either promoting immune evasion or contributing to autoimmune responses.…”