The Crystal Structure of Human Atg4b, a Processing and De-conjugating Enzyme for Autophagosome-forming Modifiers

Kumanomidou, Taichi; Mizushima, Tsunehiro; Komatsu, Masaaki; Suzuki, Atsuo; Tanida, Isei; Sou, Yu‐shin; Ueno, Takashi; Kominami, Eiki; Tanaka, Keiji; Yamane, Takashi

doi:10.1016/j.jmb.2005.11.018

Cited by 84 publications

(67 citation statements)

References 29 publications

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“…The AtATG4a putative catalytic triad sequence (C170/D264/H268) is well aligned with the corresponding HsATG4B catalytic triad sequence (C74/D278/H280) (Fig. S8C) 47 suggesting that the processing mechanism of ATG4 homologs might be similar.…”

Section: Yeast and Plant Atg4s Bind Hslc3a But Cannot Process Itmentioning

confidence: 78%

Comparative analyses of ubiquitin-like ATG8 and cysteine protease ATG4 autophagy genes in the plant lineage and cross-kingdom processing of ATG8 by ATG4

et al. 2016

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Autophagy is important for degradation and recycling of intracellular components. In a diversity of genera and species, orthologs and paralogs of the yeast Atg4 and Atg8 proteins are crucial in the biogenesis of double-membrane autophagosomes that carry the cellular cargoes to vacuoles and lysosomes. Although many plant genome sequences are available, the ATG4 and ATG8 sequence analysis is limited to some model plants. We identified 28 ATG4 and 116 ATG8 genes from the available 18 different plant genome sequences. Gene structures and protein domain sequences of ATG4 and ATG8 are conserved in plant lineages. Phylogenetic analyses classified ATG8s into 3 subgroups suggesting divergence from the common ancestor. The ATG8 expansion in plants might be attributed to whole genome duplication, segmental and dispersed duplication, and purifying selection. Our results revealed that the yeast Atg4 processes Arabidopsis ATG8 but not human LC3A (HsLC3A). In contrast, HsATG4B can process yeast and plant ATG8s in vitro but yeast and plant ATG4s cannot process HsLC3A. Interestingly, in Nicotiana benthamiana plants the yeast Atg8 is processed compared to HsLC3A. However, HsLC3A is processed when coexpressed with HsATG4B in plants. Molecular modeling indicates that lack of processing of HsLC3A by plant and yeast ATG4 is not due to lack of interaction with HsLC3A. Our in-depth analyses of ATG4 and ATG8 in the plant lineage combined with results of cross-kingdom ATG8 processing by ATG4 further support the evolutionarily conserved maturation of ATG8. Broad ATG8 processing by HsATG4B and lack of processing of HsLC3A by yeast and plant ATG4s suggest that the cross-kingdom ATG8 processing is determined by ATG8 sequence rather than ATG4.

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Section: Yeast and Plant Atg4s Bind Hslc3a But Cannot Process Itmentioning

confidence: 78%

Comparative analyses of ubiquitin-like ATG8 and cysteine protease ATG4 autophagy genes in the plant lineage and cross-kingdom processing of ATG8 by ATG4

et al. 2016

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“…A previously published x-ray crystallography study of the HsAtg4B-LC3 complex showed that Cys-74, Asp-278, and His-280 of HsAtg4B form the catalytic triad (29). The catalytic cleft of HsAtg4B is masked by a regulatory loop (residues 259 to 262) that is lifted by Phe-119 of LC3 (29,30).…”

Section: Atg-41 Is Essential For Degradation Of a Variety Of Autophagymentioning

confidence: 99%

“…The catalytic cleft of HsAtg4B is masked by a regulatory loop (residues 259 to 262) that is lifted by Phe-119 of LC3 (29,30). HsAtg4B recognizes the Phe-119 and Gly-120 residues of LC3 using the regulatory loop and Trp-142, respectively, and this recognition is essential for the processing of LC3 by HsAtg4B (Fig.…”

Section: Atg-41 Is Essential For Degradation Of a Variety Of Autophagymentioning

confidence: 99%

“…2D). Gly-258 and Ala-263 of HsAtg4B are located in the regulatory loop of Atg4, and both are involved in direct recognition of the side-chain of LC3 Phe-119 in the HsAtg4B-LC3 complex (29). Using the crystal structure of the HsAtg4B-LC3 complex (PDB ID 2ZZP), the C-terminal tail residues of LC3 were replaced with those of LGG-1.…”

Section: Atg-41 Is Essential For Degradation Of a Variety Of Autophagymentioning

confidence: 99%

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Differential Function of the Two Atg4 Homologues in the Aggrephagy Pathway in Caenorhabditis elegans

Wang

et al. 2012

Journal of Biological Chemistry

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Background:The function of multiple homologues of Atg4 in higher eukaryotes remains largely unknown. Results: We demonstrated that the two Atg4 homologues in Caenorhabditis elegans have differential enzymatic activities in processing LGG-1/Atg8 and exhibit functional redundancy. Conclusion:The two Atg4s contain redundant yet differential processing activities in the autophagy pathway. Significance: We revealed physiological function of the two Atg4 homologues in the autophagy pathway.

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“…Many drugs and compounds that modulate autophagy are currently receiving considerable attention [11,89,108]. These include, for example, autophagy inducers such as the mTORC1 inhibitor rapamycin [109] and its analogues (e.g., CCI-779 [109], RAD001 [110,111], and AP23573 [112]), mTOR kinase inhibitors (e.g., Torin 1 [113], and PP242 [114]), trehalose [115,116], carbamazepine [117], and the newly identified autophagy-inducing peptide Tatbeclin 1 [118]; autophagy inhibitors such as chloroquine [119,120] and hydroxychloroquine [121], Lys05 [122], 3-methyladenine [123] and its derivatives [124], PIK3C3 inhibitors [125], ATG4B inhibitors [126,127], and ATG7 inhibitors [128,129]. Autophagy-modulating drugs that are currently used in clinical trials are summarized in Table 2.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Autophagy and human diseases

2013

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Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation. Since the discovery of autophagy-related (Atg) genes in the 1990s, there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models. However, direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently. There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases, infectious diseases, and cancers. Here, we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases. Current autophagy-modulating compounds in clinical trials are also summarized.

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The Crystal Structure of Human Atg4b, a Processing and De-conjugating Enzyme for Autophagosome-forming Modifiers

Cited by 84 publications

References 29 publications

Comparative analyses of ubiquitin-like ATG8 and cysteine protease ATG4 autophagy genes in the plant lineage and cross-kingdom processing of ATG8 by ATG4

Comparative analyses of ubiquitin-like ATG8 and cysteine protease ATG4 autophagy genes in the plant lineage and cross-kingdom processing of ATG8 by ATG4

Differential Function of the Two Atg4 Homologues in the Aggrephagy Pathway in Caenorhabditis elegans

Autophagy and human diseases

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