title: Polymorphic Variants of Human Protein l-Isoaspartyl Methyltransferase Affect Catalytic Activity, Aggregation, and Thermal Stability: IMPLICATIONS FOR THE ETIOLOGY OF NEUROLOGICAL DISORDERS AND COGNITIVE AGING.
abstract: Protein l-isoaspartyl methyltransferase (PIMT/PCMT1), a product of the humanpcmt1gene, catalyzes repair of abnormal l-isoaspartyl linkages in age-damaged proteins. Pcmt1 knock-out mice exhibit a profound neuropathology and die 30-60 days postnatal from an epileptic seizure. Here we express 15 reported variants of human PIMT and characterize them with regard to their enzymatic activity, thermal stability, and propensity to aggregation. One mutation, R36C, renders PIMT completely inactive, whereas two others, A7P and I58V, exhibit activity that is 80-100% higher than wild type. G175R is highly prone to aggregation and has greatly reduced activity. R17S and R17H show markedly enhanced sensitivity to thermal denaturation. Based on previous studies of moderate PIMT variation in humans and mice, we predict that heterozygosity for R36C, G175R, R17S, and R17H will prove detrimental to cognitive function and successful aging, whereas homozygosity (if it ever occurs) will lead to severe neurological problems in the young.
authors.affiliation: From the Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900.
authors.forename: Charity
authors.initials: C
authors.lastname: Juang
authors.affiliation: From the Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900.
authors.forename: Baihe
authors.initials: B
authors.lastname: Chen
authors.affiliation: From the Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Bru
authors.affiliation: From the Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900.
authors.forename: Katherine
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: From the Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900.
authors.forename: Eric
authors.initials: E
authors.lastname: Huynh
authors.affiliation: From the Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Momen
authors.affiliation: From the Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900.
authors.forename: Jeungjin
authors.initials: J
authors.lastname: Kim
authors.affiliation: From the Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900 dwaswad@uci.edu.
authors.forename: Dana W
authors.identifier: 0000-0001-5098-3461
authors.initials: DW
authors.lastname: Aswad
mesh_terms: D000483:Alleles; D001921:Brain / Q000378:metabolism; D002384:Catalysis; D000066492:Cognitive Aging; D019295:Computational Biology; D004827:Epilepsy / Q000235:genetics; D005470:Fluorometry; D005838:Genotype; D006801:Humans; D026581:Isoaspartic Acid / Q000378:metabolism; D009154:Mutation; D009422:Nervous System Diseases / Q000209:etiology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013696:Temperature
chemical_list: D026581:Isoaspartic Acid; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase
keywords: S-adenosylmethionine (SAM); epilepsy; genetic polymorphism; neurological disease; protein aggregation; protein methylation; protein stability; recombinant protein expression