Cysteine protease ATG4B (ATG4B)
The protein contains 393 amino acids for an estimated molecular weight of 44294 Da.
Cysteine protease required for the cytoplasm to vacuole transport (Cvt) and autophagy. Cleaves the C-terminal amino acid of ATG8 family proteins MAP1LC3, GABARAPL1, GABARAPL2 and GABARAP, to reveal a C-terminal glycine. Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy. Has also an activity of delipidating enzyme for the PE-conjugated forms. (updated: March 4, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs7601000 |
Biological Process
Autophagosome assembly
Autophagy
Autophagy of mitochondrion
Autophagy of nucleus
C-terminal protein lipidation
Cellular response to nitrogen starvation
Macroautophagy
Positive regulation of autophagy
Positive regulation of protein catabolic process
Protein delipidation
Protein processing
Protein targeting to membrane
Protein transport
Proteolysis
The reference OMIM entry for this protein is 611338
Autophagy 4, s. cerevisiae, homolog of, b; atg4b
Apg4, s. cerevisiae, homolog of, b; apg4b
Autophagin 1
Autl1
Kiaa0943
DESCRIPTION
Autophagy is the biologic process leading to intracellular destruction of endogenous proteins and removal of damaged organelles. ATG4B is a homolog of yeast Apg4, a cysteine protease involved in autophagy (Marino et al., 2003).CLONING
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned ATG4B, which they designated KIAA0943. The transcript contains a repetitive element in its 3-prime UTR. RT-PCR ELISA detected moderate expression in all adult and fetal tissues and specific brain regions examined. By searching for sequences similar to yeast Apg4, followed by PCR of human cDNA libraries, Marino et al. (2003) cloned ATG4B, which they called autophagin-1. The deduced 393-amino acid protein contains a putative active-site cysteine at position 74. ATG4B shares significant similarity with yeast Apg4, except for divergence at its N- and C-terminal ends. The absence of an N-terminal signal sequence suggests that ATG4B is a cytoplasmic enzyme. Northern blot analysis detected a 4.5-kb transcript that was highly expressed in skeletal muscle, with lower expression in heart, liver, and pancreas. No expression was detected in fetal tissues. ATG4B was widely expressed in tumor cell lines.GENE FUNCTION
Marino et al. (2003) showed that autophagin-1 could complement Apg4 deficiency in yeast, restoring the phenotypic and biochemical characteristics of autophagic cells. Apg8 is a ubiquitin-like protein involved in autophagy in yeast, and there are at least 4 mammalian Apg8 homologs: GATE16 (GABARAPL2; 607452), GABARAP (605125), MAP1LC3 (see 601242), and APG8L (GABARAPL1; 607420). Hemelaar et al. (2003) found that mouse Atg4b acted on the C termini of these 4 Atg8 homologs, and that the reaction required the active-site cysteine of Atg4b. Although the amino acid sequences of these Apg8 homologs differ from one another by as much as 71%, their affinities for Atg4b were roughly comparable in competition experiments.BIOCHEMICAL FEATURES
Sugawara et al. (2005) reported the crystal structure of human ATG4B at 1.9-angstrom resolution. The ATG4B structure showed a classical papain (see CTSF; 603539)-like fold and a small alpha/beta-fold domain, similar to those of ubiquitin-specific proteases, that may be the binding site for Atg8 homologs. The active-site cleft of ATG4B, which contains the catalytic triad of cys74, asp278, and his280, is masked by a loop, implying that a conformational change occurs upon substrate binding. Mutation of cys74, asp278, or his280 resulted in complete loss of protease activity.MAPPING
By genomic sequence analysis, Marino et al. (2003) mapped the ATG4B gene to chromosome 2q37. ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 611338 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed