Characterization of Three cDNAs Encoding Two Isozymes of an Isoaspartyl Protein Carboxyl Methyltransferase from Human Erythroid Leukemia Cells1

Takeda, Ryohei; Mizobuchi, Masahiro; Murao, Koji; Sato, Makoto; Takahara, Jiro

doi:10.1093/oxfordjournals.jbchem.a124763

Cited by 5 publications

(3 citation statements)

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“…There are two known isozymes of HPIMT attributable to differential mRNA splicing (Takeda et al 1995). Isozyme 1 has one less amino acid at the C‐terminal and ends with WK, whereas isozyme 2 ends with DEL, which is a known endoplasmic reticulum retention factor.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of human L‐isoaspartyl‐O‐methyl‐transferase with S‐adenosyl homocysteine at 1.6‐Å resolution and modeling of an isoaspartyl‐containing peptide at the active site

et al. 2002

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Spontaneous formation of isoaspartyl residues (isoAsp) disrupts the structure and function of many normal proteins. Protein isoaspartyl methyltransferase (PIMT) reverts many isoAsp residues to aspartate as a protein repair process. We have determined the crystal structure of human protein isoaspartyl methyltransferase (HPIMT) complexed with adenosyl homocysteine (AdoHcy) to 1.6-Å resolution. The core structure has a nucleotide binding domain motif, which is structurally homologous with the N-terminal domain of the bacterial Thermotoga maritima PIMT. Highly conserved residues in PIMTs among different phyla are placed at positions critical to AdoHcy binding and orienting the isoAsp residue substrate for methylation. The AdoHcy is completely enclosed within the HPIMT and a conformational change must occur to allow exchange with adenosyl methionine (AdoMet). An ordered sequential enzyme mechanism is supported because C-terminal residues involved with AdoHcy binding also form the isoAsp peptide binding site, and a change of conformation to allow AdoHcy to escape would preclude peptide binding. Modeling experiments indicated isoAsp groups observed in some known protein crystal structures could bind to the HPIMT active site.

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Section: Resultsmentioning

confidence: 99%

Crystal structure of human L‐isoaspartyl‐O‐methyl‐transferase with S‐adenosyl homocysteine at 1.6‐Å resolution and modeling of an isoaspartyl‐containing peptide at the active site

et al. 2002

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“…PIMT is present in all vertebrate tissues and represents the major protein methyltransferase in the brain, testis, erythrocytes and eye (Yamamoto et al, 1998). PIMT is normally an intracellular enzyme that exists in two isoforms due to differential mRNA splicing (Takeda et al, 1995). The C-terminus of one isoenzyme ends with the sequence RWK, whereas the other isoform ends with RDEL, a known endoplasmic reticulum retention sequence (MacLaren et al, 1992).…”

Section: Regulation Of Isoasp Formation In Tissuesmentioning

confidence: 99%

Isoaspartate-dependent molecular switches for integrin–ligand recognition

Corti¹,

Curnis²

2011

Journal of Cell Science

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Formation of isoAsp in ECM proteins and its functional effects Formation of isoAsp and ECM protein damageThe formation of isoAsp residues at Asn or Asp residues in proteins is generally considered a degradation reaction as a consequence of protein aging. IsoAsp formation has been shown to occur in ECM proteins, including collagen types I and III, in fibronectin, in -crystallin and in the ECM of the mammalian brain (Lanthier and Desrosiers, 2004;Lindner and Helliger, 2001; Reissner and Aswad, SummaryIntegrins are cell-adhesion receptors that mediate cell-extracellular-matrix (ECM) and cell-cell interactions by recognizing specific ligands. Recent studies have shown that the formation of isoaspartyl residues (isoAsp) in integrin ligands by asparagine deamidation or aspartate isomerization could represent a mechanism for the regulation of integrin-ligand recognition. This spontaneous posttranslational modification, which might occur in aged proteins of the ECM, changes the length of the peptide bond and, in the case of asparagine, also of the charge. Although these changes typically have negative effects on protein function, recent studies suggested that isoAsp formation at certain Asn-Gly-Arg (NGR) sites in ECM proteins have a gain-of-function effect, because the resulting isoAsp-Gly-Arg (isoDGR) sequence can mimic Arg-Gly-Asp (RGD), a well-known integrin-binding motif. Substantial experimental evidence suggests that the NGR-to-isoDGR transition can occur in vitro in natural proteins and in drugs containing this motif, thereby promoting integrin recognition and cell adhesion. In this Commentary, we review these studies and discuss the potential effects that isoAsp formation at NGR, DGR and RGD sites might have in the recognition of integrins by natural ligands and by drugs that contain these motifs, as well as their potential biological and pharmacological implications.

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“…The type I isoform ends in the sequence -RWK and has a pI of 6.6 while the type II isoform ends in RDEL and is more acidic, with a pI of 5.5 (Ota et al 1988;Takeda et al 1995). A third, minor isoform of human PIMT with a pI value intermediate between the two major forms has been discovered but has not yet been fully characterized (MacLaren et al 1992).…”

Section: Down-regulation Of Pimt In the Hippocampus Of Epileptic Patimentioning

confidence: 99%

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

Lanthier

Bouthillier

Lapointe

et al. 2002

Journal of Neurochemistry

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Protein L-isoaspartyl methyltransferase (PIMT) repairs the damaged proteins which have accumulated abnormal aspartyl residues during cell aging. Gene targeting has elucidated a physiological role for PIMT by showing that mice lacking PIMT died prematurely from fatal epileptic seizures. Here we investigated the role of PIMT in human mesial temporal lobe epilepsy. Using surgical specimens of hippocampus and neocortex from controls and epileptic patients, we showed that PIMT activity and expression were 50% lower in epileptic hippocampus than in controls but were unchanged in neocortex. Although the protein was down-regulated, PIMT mRNA expression was unchanged in epileptic hippocampus, suggesting post-translational regulation of the PIMT level. Moreover, several proteins with abnormal aspartyl residues accumulate in epileptic hippocampus. Microtubules component b-tubulin, one of the major PIMT substrates, had an increased amount (two-fold) of L-isoaspartyl residues in the epileptic hippocampus. These results demonstrate that the down-regulation of PIMT in epileptic hippocampus leads to a significant accumulation of damaged tubulin that could contribute to neuron dysfunction in human mesial temporal lobe epilepsy.

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Characterization of Three cDNAs Encoding Two Isozymes of an Isoaspartyl Protein Carboxyl Methyltransferase from Human Erythroid Leukemia Cells1

Cited by 5 publications

References 0 publications

Crystal structure of human L‐isoaspartyl‐O‐methyl‐transferase with S‐adenosyl homocysteine at 1.6‐Å resolution and modeling of an isoaspartyl‐containing peptide at the active site

Crystal structure of human L‐isoaspartyl‐O‐methyl‐transferase with S‐adenosyl homocysteine at 1.6‐Å resolution and modeling of an isoaspartyl‐containing peptide at the active site

Isoaspartate-dependent molecular switches for integrin–ligand recognition

Down‐regulation of protein l‐isoaspartyl methyltransferase in human epileptic hippocampus contributes to generation of damaged tubulin

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