Altered Activity, Social Behavior, and Spatial Memory in Mice Lacking the NTAN1p Amidase and the Asparagine Branch of the N-End Rule Pathway

Kwon, Yong Tae; Balogh, Seth A.; Davydov, Ilia V.; Kashina, Anna; Yoon, Jong‐Hwan; Xie, Youming; Gaur, Arti; Hyde, Lynn A.; Denenberg, Victor H.; Varshavsky, Alexander

doi:10.1128/mcb.20.11.4135-4148.2000

Cited by 93 publications

(134 citation statements)

References 64 publications

(86 reference statements)

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…4(#9, #12, #18, #22, #23, #24), and data not shown]. This fact and the above genetic results [270][271][272][273][274] strongly suggest a role of the Arg/N-end rule pathway in memory processes.…”

Section: The Fg Hypothesis and Settings Other Than Sleepmentioning

confidence: 72%

“…2(A)], showed that these mice had significant defects in learning and long-term memory. 272 The recent discovery and molecular characterization of the Gln-specific Ntaq1 Nt Q -amidase, another component of the Arg/N-end rule pathway [ Fig. 2(A)], has revealed that the previously identified fly mutant termed tungus, which had impaired long-term memory, 273 was apparently a null mutant in the Drosophila Ntaq1 Nt Q -amidase.…”

Section: The Fg Hypothesis and Settings Other Than Sleepmentioning

confidence: 99%

See 1 more Smart Citation

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

Self Cite

View full text Add to dashboard Cite

Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

show abstract

Section: The Fg Hypothesis and Settings Other Than Sleepmentioning

confidence: 72%

Section: The Fg Hypothesis and Settings Other Than Sleepmentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…1) suggests that Arg became a Nd p residue late in evolution of the N-end rule pathway, after the emergence of eukaryotes. The absence of sequelogy (32) between the yeast (S. cerevisiae) NTA1 N-terminal amidase (Ntamidase) and the mammalian Asn-specific NTAN1 Nt N -amidase (15,16) suggests that the tertiary destabilizing N-terminal residues Asn and Gln (Fig. 1 A) became part of the N-end rule still later, after the divergence of fungal and metazoan lineages.…”

Section: Identical Specificities Of Ate1 and Atel1 May Be The Results Ofmentioning

confidence: 99%

“…1). In eukaryotes, N-terminal Asn (N) and Gln (Q) are tertiary destabilizing residues in that they function, through enzymatic deamidation (15,16), to yield the secondary destabilizing N-terminal residues (Nd s ) Asp (D) and Glu (E) (Fig. 1 A).…”

mentioning

confidence: 99%

Aminoacyl-transferases and the N-end rule pathway of prokaryotic/eukaryotic specificity in a human pathogen

Graciet

Hu²,

Piatkov³

et al. 2006

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

Self Cite

115

View full text Add to dashboard Cite

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Primary destabilizing N-terminal residues (Nd p ) are recognized directly by the targeting machinery. The recognition of secondary destabilizing N-terminal residues (Nd s ) is preceded by conjugation of an Nd p residue to Nd s of a polypeptide substrate. In eukaryotes, ATE1 -encoded arginyl-transferases (R D,E,C* -transferases) conjugate Arg (R), an Nd p residue, to Nd s residues Asp (D), Glu (E), or oxidized Cys residue (C*). Ubiquitin ligases recognize the N-terminal Arg of a substrate and target the (ubiquitylated) substrate to the proteasome. In prokaryotes such as Escherichia coli , Nd p residues Leu (L) or Phe (F) are conjugated, by the aat -encoded Leu/Phe-transferase (L/F K,R -transferase), to N-terminal Arg or Lys, which are Nd s in prokaryotes but Nd p in eukaryotes. In prokaryotes, substrates bearing the Nd p residues Leu, Phe, Trp, or Tyr are degraded by the proteasome-like ClpAP protease. Despite enzymological similarities between eukaryotic R D,E,C* -transferases and prokaryotic L/F K,R -transferases, there is no significant sequelogy (sequence similarity) between them. We identified an aminoacyl-transferase, termed Bpt, in the human pathogen Vibrio vulnificus . Although it is a sequelog of eukaryotic R D,E,C* -transferases, this prokaryotic transferase exhibits a “hybrid” specificity, conjugating Nd p Leu to Nd s Asp or Glu. Another aminoacyl-transferase, termed ATEL1, of the eukaryotic pathogen Plasmodium falciparum , is a sequelog of prokaryotic L/F K,R -transferases (Aat), but has the specificity of eukaryotic R D,E,C* -transferases (ATE1). Phylogenetic analysis suggests that the substrate specificity of R-transferases arose by two distinct routes during the evolution of eukaryotes.

show abstract

“…31 NTAN1 encodes for aspargine specific N-terminal amidase, and mice lacking this enzyme show abnormalities in spontaneous activity, spatial memory and a socially conditioned exploratory phenotype. 32 Although the loss of copy number in these genes has resulted in neurological manifestations in animal models, the phenotypic consequences of gain of copy number is still unclear. Thus, the role of duplication of these genes in behavioral and cognitive impairments is at best speculative.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic manifestations of copy number variation in chromosome 16p13.11

et al. 2010

View full text Add to dashboard Cite

The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.

show abstract

Altered Activity, Social Behavior, and Spatial Memory in Mice Lacking the NTAN1p Amidase and the Asparagine Branch of the N-End Rule Pathway

Cited by 93 publications

References 64 publications

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Aminoacyl-transferases and the N-end rule pathway of prokaryotic/eukaryotic specificity in a human pathogen

Phenotypic manifestations of copy number variation in chromosome 16p13.11

Contact Info

Product

Resources

About