Biochemical and enzymatic properties of the M1 family of aminopeptidases involved in the regulation of blood pressure

Tsujimoto, Masafumi; Goto, Yoshikuni; Maruyama, Masato; Hattori, Akira

doi:10.1007/s10741-007-9064-8

Cited by 64 publications

(49 citation statements)

References 59 publications

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“…ERAP1 belongs to the gluzincin family of metalloproteases and shares the common H-E-X-X-H-X 18 -E zinc-binding motif (24). The catalytic zinc ion is coordinated by His 353 , His 357 , Glu 376 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Kochan

Krojer

Harvey

et al. 2011

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

226

286

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Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path. ERAP1 is a zinc-metallopeptidase with typical H-E-X-X-H-ðXÞ 18 -E zinc binding and G-A-M-E-N motifs characteristic for members of the gluzincin protease family. The structures reveal extensive domain movements, including an active site closure as well as three different open conformations, thus providing insights into the catalytic cycle. A K 528 R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.antigen presentation | ERAP1 mechanism | MHC restriction

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Section: Resultsmentioning

confidence: 99%

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Kochan

Krojer

Harvey

et al. 2011

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

226

286

View full text Add to dashboard Cite

show abstract

“…They were compared with normal fetal esophageal and tracheal tissues (negative control) and with fetal testis, thyroid, and liver tissues (positive control) (24). Formalin-fixed paraffin-embedded tissues were obtained from archival autopsy.…”

Section: Prenatal Diagnosis Of Esophageal Atresiamentioning

confidence: 99%

Specific biochemical amniotic fluid pattern of fetal isolated esophageal atresia

et al. 2013

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“…13,20 Several studies have been performed to understand the role of the active site residues in many M1 class aminopeptidases within the substrate binding and metal binding regions that comprise the GXMEN and HEXXH-(X18)-E motifs. 21 However, there has been no study so far to address the interface of Domains I and II that constitute substrate binding region. In this study, we describe the role of a couple of residues on the enzyme activity and stability, one each from Domains I and II within the interface that form a buried salt bridge.…”

Section: Discussionmentioning

confidence: 99%

Glu121‐Lys319 salt bridge between catalytic and N‐terminal domains is pivotal for the activity and stability of Escherichia coli aminopeptidase N

et al. 2012

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Escherichia coli aminopeptidase N (ePepN) belongs to the gluzincin family of M1 class metalloproteases that share a common primary structure with consensus zinc binding motif (HEXXH-(X18)-E) and an exopeptidase motif (GXMEN) in the active site. There is one amino acid, E121 in Domain I that blocks the extended active site grove of the thermolysin like catalytic domain (Domain II) limiting the substrate to S1 pocket. E121 forms a part of the S1 pocket, while making critical contact with the amino-terminus of the substrate. In addition, the carboxylate of E121 forms a salt bridge with K319 in Domain II. Both these residues are absolutely conserved in ePepN homologs. Analogous Glu-Asn pair in tricon interacting factor F3 (F3) and Gln-Asn pair in human leukotriene A 4 hydrolase (LTA 4 H) are also conserved in respective homologs. Mutation of either of these residues individually or together substantially reduced or entirely eliminated enzymatic activity. In addition, thermal denaturation studies suggest that the mutation at K319 destabilizes the protein as much as by 3.7°C, while E121 mutants were insensitive. Crystal structure of E121Q mutant reveals that the enzyme is inactive due to the reduced S1 subsite volume. Together, data presented here suggests that ePepN, F3, and LTA 4 H homologs adopted a divergent evolution that includes E121-K319 or its analogous pairs, and these cannot be interchanged.

show abstract

Biochemical and enzymatic properties of the M1 family of aminopeptidases involved in the regulation of blood pressure

Cited by 64 publications

References 59 publications

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Specific biochemical amniotic fluid pattern of fetal isolated esophageal atresia

Glu121‐Lys319 salt bridge between catalytic and N‐terminal domains is pivotal for the activity and stability of Escherichia coli aminopeptidase N

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