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ATG5

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ATG5, also known as autophagy protein 5, is a protein that, in humans, is encoded by the ATG5 gene on Chromosome 6.

ATG5 is an E3 ubiquitin-like ligase that forms a multimeric complex with ATG12 and ATG16L1 involved in autophagy and autophagic cell death through the extention of the phagophoric membrane in autophagic vesicles. [1][2][3]ATG5 can also act as a pro-apoptotic molecule targeted to the mitochondria.[4] Under low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin.[5][6]

ATG5 is known to be regulated via various stress induced transcription factors and protein kinases.

 Structure

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ATG5 comprises of three domains: a ubiquitin-like N-terminal domain (UblA),  a helix-rich domain (HR) and a ubiquitin-like C-terminal domain (UblB). The three domains are connected by two linker regions (L1 and L2). ATG5 also has an alpha-helix at the N terminus where on Lysine 130 conjugation with ATG12 occurs.[7] Both UblA and UbLB are comprised of a five-stranded beta-sheet and two alpha-helices, a feature conserved in most ubiquitin and ubiquitin-like proteins. HR is comprised of three long and one short alpha helices, forming a helix-bundle structure.[8]

Regulation

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ATG5 is regulated by the p73 from the p53 family of transcription factors. DNA damage induces the p300 acetylase to acetylate p73 with the assistance of c-ABL tyrosine kinase. p73 translocates to the nucleus and acts as a transcription factor for ATG5 as well as other apoptotic and autophagic genes.[9]

Programmed Cell Death Protein 4 (PDCD4) is known to inhibit ATG5 expression via inhibition of protein translation. Two MA3 domains on PDCD4 bind to RNA-helicase EIF4A, preventing translation of ATG5 mRNA.[10]

Many protein kinases can regulate activity of the ATG5 protein. Phosphorylation by various kinases are required in order to achieve its active conformation. Under cell stress conditions, the growth arrest and DNA damage 45 beta (Gadd45ß) protein will interact with MAPK/ERK kinase kinase 4 (MEKK4) to form the Gadd45ß-MEKK4 signaling complex. This complex then activates and selectively targets p38 MAPK to the autophagosome to phosphorylate ATG5 at threonine 75. This leads to the inactivation of ATG5 and ihibition of autophagy.[11]

ATG5 can also be regulated post translationally by microRNA. [12]

Function

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Autophagy

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The ATG12-ATG5:ATG16L complex is responsible for elongation of the phagophore in the autophagy pathway. ATG12 is first activated by ATG7, proceeded by the conjugation of ATG5 to the complex by ATG10 via a unbiquitination-like enzymatic process. The ATG12-ATG5 then forms a homo-oligomeric complex with ATG16L.[13] With the help of ATG7 and ATG3, the ATG12-ATG5:ATG16L complex conjugates the C terminus of LC3-I to phosphatidylethanolamine in the phospholipid bilayer, allowing LC3 to associate with the membranes of the phagophore, becoming LC3-II. After formation of the autophagosome, the ATG12-ATG5:ATG16L complex dissociates from the autophagosome.[14][15][16]

Apoptosis

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In instances of spontaneous apoptosis or induction of apoptosis via staurosporine, HL-60, or EOL cells, ATG5 undergoes N-terminal cleavage by Calpain-1 and Calpain-2. The cleaved ATG5 translocates from the cytosol to the mitochondria, where it interacts with Bcl-xL, triggering the release of Cytochrome c and activating caspases leading to the apoptotic pathway. [17][18]

Cell Cycle Arrest

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In response to DNA damage, ATG5 expression is upregulated, increasing autophagy, preventing caspase activation and apoptosis. ATG5 is also responsible for G2/M arrest and mitotic catastrophe by leading to the phosphorylation of CDK1 and CHEK2, two important regulators of cell cycle arrest. [19] Furthermore ATG5 is capable of translocating to the nucleus and interacting with survivin to disturb chromosome segregation by antagonistically competing with the ligand Aurora B.[20][21][22]

Clinical Significance

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As a key regulator of autophagy, any suppression of the ATG5 protein or loss-of-functuion mutations in the ATG5 gene will negatively affect autophagy. As a result, deficiencies in the ATG5 protein and variations in the gene have been associated with various inflammatory and degenerative diseases. Polymorphisms with the ATG5 gene have been associated with Behçet's disease,[23] systemic lupus erythematosus,[24] and lupus nephritis.[25] Mutations in the gene promoter for the ATG5 gene have been associated with sporadic Parkinson's disease[26] and childhood asthma.[27] Downregulation of ATG5 protein and mutations in the ATG5 gene have also been linked with gastrointestinal[28] and colorectal[29] cancers as ATG5 plays a role in both cell apoptosis and cell cycle arrest. Upregulation of ATG5 on the other hand has been shown to supress melanoma tumorigenesis through induction of cell senescence[30] and plays a protective role in M. tuberculosis infections by preventing PMN-mediated immunopathology.[31]

An ATG5-/- mutation in mice is known to be embryonic lethal.[32] When the mutation is induced only in mice neurons or hepatocytes, there is an accumulation of ubiquitin-positive inclusion bodies and a decrease in cell function.[33] Overexpression of ATG5 on the otherhand has been linked to extend mouse lifespan.

Article: DNA methyltransferase

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  • The structure and mechanism of action from the m6A methytransferase seems to be overrepresented. This might be because it is better understood than the other groups of MTases?

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  • Wikipedia discusses more about the various different groups and types of DNA methyltrasferases, and covers their specific structure and mechanisms of actions. In class we talk more about the targets in the DNA of methyltransferases, and the effects of their methylation.
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