A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration

Chu, Jessie; Hong, Nancy A.; Masuda, Cláudio A.; Jenkins, Brian V.; Nelms, Keats; Goodnow, Christopher C.; Glynne, Richard; Wu, Hua Hsi; Masliah, Eliezer; Joazeiro, Claudio A.P.; Kay, Steve A.

doi:10.1073/pnas.0812819106

Cited by 210 publications

(193 citation statements)

References 42 publications

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“…Rather, this region, predicted to be composed of a long stretch of HEAT-or ARM-type α-helical repeats (10), appears to function as a linker mediating communication between Ltn1's ends bound to distal sites on the ribosome. This observation may explain the apparent lack of sequence conservation of the middle region among Ltn1 orthologs (4) and why the ENU-induced 13-aa internal deletion in the corresponding region of mouse listerin results in a hypomorphic allele and neurodegeneration (6).…”

Section: Significancementioning

confidence: 99%

“…Mutation of the Ltn1 mouse ortholog, listerin, causes neurodegeneration (6), suggesting an important function for this process. Ltn1 works together with several cofactors as part of the ribosome-associated quality control complex (RQC) (7)(8)(9) and appears to first associate with nascent chain-stalled 60S subunits together with two proteins of unknown function, Tae2 and Rqc1 (7,9).…”

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confidence: 99%

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Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex

Lyumkis

Passos

Tahara

et al. 2014

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

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All organisms have evolved mechanisms to manage the stalling of ribosomes upon translation of aberrant mRNA. In eukaryotes, the large ribosomal subunit-associated quality control complex (RQC), composed of the listerin/Ltn1 E3 ubiquitin ligase and cofactors, mediates the ubiquitylation and extraction of ribosome-stalled nascent polypeptide chains for proteasomal degradation. How RQC recognizes stalled ribosomes and performs its functions has not been understood. Using single-particle cryoelectron microscopy, we have determined the structure of the RQC complex bound to stalled 60S ribosomal subunits. The structure establishes how Ltn1 associates with the large ribosomal subunit and properly positions its E3-catalytic RING domain to mediate nascent chain ubiquitylation. The structure also reveals that a distinguishing feature of stalled 60S particles is an exposed, nascent chainconjugated tRNA, and that the Tae2 subunit of RQC, which facilitates Ltn1 binding, is responsible for selective recognition of stalled 60S subunits. RQC components are engaged in interactions across a large span of the 60S subunit surface, connecting the tRNA in the peptidyl transferase center to the distally located nascent chain tunnel exit. This work provides insights into a mechanism linking translation and protein degradation that targets defective proteins immediately after synthesis, while ignoring nascent chains in normally translating ribosomes.Tae2/Nemf | translational surveillance | protein quality control | cryo-EM | listerin/Ltn1 E3 ubiquitin ligase D uring the canonical termination and recycling steps of translation, stop codon recognition triggers factor-mediated hydrolysis of the nascent peptidyl-tRNA conjugate, nascent chain release, and ribosome splitting (1-3). Conversely, translation of aberrant mRNA, such as mRNA lacking stop codons ("nonstop mRNA"), renders 80S ribosomes stalled with nascent polypeptides (1-3). Furthermore, "nonstop proteins" cannot be corrected by quality control chaperones and have the potential to interfere with cellular function (3, 4). Not surprisingly, defective termination and recycling are under surveillance by a variety of mechanisms (1-3). In eukaryotes, "rescue factors" homologous to termination factors promote dissociation of translationally halted ribosomes in a stop codon-independent manner (5). However, because rescue factors lack peptidyl-tRNA hydrolase activity, their action results in nascent chains remaining stalled on the released 60S subunit.Ltn1 is the critical E3 ligase mediating ubiquitylation of aberrant proteins that become stalled on ribosomes during translation (4). Mutation of the Ltn1 mouse ortholog, listerin, causes neurodegeneration (6), suggesting an important function for this process. Ltn1 works together with several cofactors as part of the ribosome-associated quality control complex (RQC) (7-9) and appears to first associate with nascent chain-stalled 60S subunits together with two proteins of unknown function, Tae2 and Rqc1 (7, 9). Ltn1-mediated ubiquitylation of t...

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Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex

Lyumkis

Passos

Tahara

et al. 2014

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

Self Cite

113

130

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“…Ltn1 functions by associating with ribosomes and mediating the ubiquitylation and subsequent degradation of translationally arrested nonstop proteins (7). Experiments in yeast showed that the absence of Ltn1 leads to the toxic accumulation of such proteins, which may explain the embryonic lethality and neurodegenerative phenotypes of Ltn1/ Listerin-mutant mice (7,8). The elucidation of Ltn1's role in yeast has identified how nonstop protein levels are controlled in eukaryotic cells, a process mechanistically distinct from the bacterial system.…”

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confidence: 99%

Single-particle EM reveals extensive conformational variability of the Ltn1 E3 ligase

Lyumkis

Doamekpor

Bengtson

et al. 2013

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

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Ltn1 is a 180-kDa E3 ubiquitin ligase that associates with ribosomes and marks certain aberrant, translationally arrested nascent polypeptide chains for proteasomal degradation. In addition to its evolutionarily conserved large size, Ltn1 is characterized by the presence of a conserved N terminus, HEAT/ARM repeats predicted to comprise the majority of the protein, and a C-terminal catalytic RING domain, although the protein's exact structure is unknown. We used numerous single-particle EM strategies to characterize Ltn1's structure based on negative stain and vitreous ice data. Two-dimensional classifications and subsequent 3D reconstructions of electron density maps show that Ltn1 has an elongated form and presents a continuum of conformational states about two flexible hinge regions, whereas its overall architecture is reminiscent of multisubunit cullin-RING ubiquitin ligase complexes. We propose a model of Ltn1 function based on its conformational variability and flexibility that describes how these features may play a role in cotranslational protein quality control.conformational heterogeneity | Ltn1/Listerin | RING E3 ubiquitin ligase | translational surveillance | neurodegenerative disease

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“…Mice lacking the ribosome-associated quality control ubiquitin ligase (E3) Listerin exhibit severe neurodegeneration and impaired motor function (2). Under genetic or pharmacological conditions of excessive NS protein production, Saccharomyces cerevisiae lacking the yeast homolog (Rkr1/Ltn1) display a significant growth defect (3).…”

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confidence: 99%

Rkr1/Ltn1 Ubiquitin Ligase-mediated Degradation of Translationally Stalled Endoplasmic Reticulum Proteins

Crowder

Geigges

Gibson

et al. 2015

Journal of Biological Chemistry

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Background: Translationally stalled proteins (including those aberrantly translated beyond their stop codons) pose dangers for eukaryotic cells. Results: The ubiquitin ligase Rkr1/Ltn1 targets translationally stalled ER-associated proteins for degradation. Conclusion: Cytosolic and ER-associated translationally stalled proteins are targeted for destruction by related mechanisms. Significance: Mechanisms regulating the degradation of translationally stalled ER-associated proteins may represent therapeutic targets for human disease.

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A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration

Cited by 210 publications

References 42 publications

Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex

Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex

Single-particle EM reveals extensive conformational variability of the Ltn1 E3 ligase

Rkr1/Ltn1 Ubiquitin Ligase-mediated Degradation of Translationally Stalled Endoplasmic Reticulum Proteins

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