Recognition of an Ala-rich C-degron by the E3 ligase Pirh2

Wang, Xiaolu; Li, Yao; Yan, Xiao‐Jie; Yang, Qing; Zhang, Bing; Zhang, Ying; Yuan, Xinxin; Jiang, Chenhao; Chen, Dongxing; Liu, Quanyan; Liu, Tong; Mi, Wenyi; Yu, Ying; Cheng, Dong

doi:10.1038/s41467-023-38173-6

Cited by 7 publications

(2 citation statements)

References 64 publications

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“…The nuclease Vms1/ANKZF1 and peptidyl-tRNA hydrolases have been proposed to cleave the P-site tRNA and facilitate NC release [26][27][28][29] . Once off the ribosome, CAT tails act as C-terminal degrons that mark stalled NCs for proteasomal degradation, serving as a backup pathway in case Ltn1p does not successfully target the NC 22,[30][31][32] (Figure 1A). In bacteria, CAT tails function as degrons 13,18 and have been proposed to enhance NC release from the large ribosomal subunit 29 .…”

Section: Introductionmentioning

confidence: 99%

Mechanochemical forces regulate the composition and fate of stalled nascent chains

Khan,

Vinayak,

Sitron

et al. 2024

Preprint

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The ribosome-associatedqualitycontrol (RQC) pathway resolves stalled ribosomes. As part of RQC, stalled nascent polypeptide chains (NCs) are appended withCArboxy-Terminal amino acids (CAT tails) in an mRNA-free, non-canonical elongation process. CAT tail composition includes Ala, Thr, and potentially other residues. The relationship between CAT tail composition and function has remained unknown. Using biochemical approaches in yeast, we discovered that mechanochemical forces on the NC regulate CAT tailing. We propose CAT tailing initially operates in an “extrusion mode” that increases NC lysine accessibility for on-ribosome ubiquitination. Thr in CAT tails enhances NC extrusion by preventing formation of polyalanine, which can form α-helices. After NC ubiquitylation, pulling forces on the NC switch CAT tailing to an Ala-only “release mode” which facilitates nascent chain release from large ribosomal subunits and NC degradation. Failure to switch from extrusion to release mode leads to accumulation of NCs on large ribosomal subunits and proteotoxic aggregation of Thr-rich CAT tails.One sentence summaryMechanochemical forces regulate the composition of CAT tails to extrude or release stalled nascent chains and recycle ribosomes.

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Section: Introductionmentioning

confidence: 99%

Mechanochemical forces regulate the composition and fate of stalled nascent chains

Khan,

Vinayak,

Sitron

et al. 2024

Preprint

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“…KLHDC2 binds to C-degrons ending with diglycine ( 17 , 18 ); FEM1B and FEM1A/1C recognize C-degrons ending with arginine (Arg/C-degrons), with upstream sequences playing a role in selectivity ( 19 – 21 ). Very recently, it was reported that Cereblon, the SR of CRL4, targets the C-terminal cyclic imide degron( 22 ), Gln/C-degron is recognized by TRIM7 ( 23 , 24 ), Ala tails function as C-degron to recruit CRL2 KLHDC10 or Pirh2 ( 25 , 26 ), and CRL4 DCAF12 targets di-Glu C-degron ( 27 ). In the above C-degron pathway branches, sequence-specific C-terminal residues are engaged by an SR of the multisubunit E3 ligase or a functional domain of a single E3 ligase.…”

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confidence: 99%

Molecular basis for C-degron recognition by CRL2^APPBP2ubiquitin ligase

Zhao,

Olmayev-Yaakobov,

et al. 2023

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

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E3 ubiquitin ligases determine the specificity of eukaryotic protein degradation by selective binding to destabilizing protein motifs, termed degrons, in substrates for ubiquitin-mediated proteolysis. The exposed C-terminal residues of proteins can act as C-degrons that are recognized by distinct substrate receptors (SRs) as part of dedicated cullin-RING E3 ubiquitin ligase (CRL) complexes. APPBP2, an SR of Cullin 2-RING ligase (CRL2), has been shown to recognize R-x-x-G/C-degron; however, the molecular mechanism of recognition remains elusive. By solving several cryogenic electron microscopy structures of active CRL2 APPBP2 bound with different R-x-x-G/C-degrons, we unveiled the molecular mechanisms underlying the assembly of the CRL2 APPBP2 dimer and tetramer, as well as C-degron recognition. The structural study, complemented by binding experiments and cell-based assays, demonstrates that APPBP2 specifically recognizes the R-x-x-G/C-degron via a bipartite mechanism; arginine and glycine, which play critical roles in C-degron recognition, accommodate distinct pockets that are spaced by two residues. In addition, the binding pocket is deep enough to enable the interaction of APPBP2 with the motif placed at or up to three residues upstream of the C-end. Overall, our study not only provides structural insight into CRL2 APPBP2 -mediated protein turnover but also serves as the basis for future structure-based chemical probe design.

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Conserved quality control mechanisms of mitochondrial protein import

Borgert,

Becker,

den Brave

2024

J of Inher Metab Disea

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Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co‐factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900–1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non‐imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non‐imported precursor proteins from the TOM channel. The highly conserved ubiquitin‐proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria‐localized and cytosolic proteins to prevent proteotoxic stress in the cell.

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Recognition of an Ala-rich C-degron by the E3 ligase Pirh2

Cited by 7 publications

References 64 publications

Mechanochemical forces regulate the composition and fate of stalled nascent chains

Mechanochemical forces regulate the composition and fate of stalled nascent chains

Molecular basis for C-degron recognition by CRL2^APPBP2ubiquitin ligase

Conserved quality control mechanisms of mitochondrial protein import

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Recognition of an Ala-rich C-degron by the E3 ligase Pirh2

Cited by 7 publications

References 64 publications

Mechanochemical forces regulate the composition and fate of stalled nascent chains

Mechanochemical forces regulate the composition and fate of stalled nascent chains

Molecular basis for C-degron recognition by CRL2APPBP2ubiquitin ligase

Conserved quality control mechanisms of mitochondrial protein import

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Product

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Molecular basis for C-degron recognition by CRL2^APPBP2ubiquitin ligase