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Autophagy-related protein complex of Saccharomyces cerevisiae (Munakata and Klionsky, 2010).  Different levels of autophagy activity reflect differences in autophagosome formation, correlating with the delivery of Atg9 to the PAS. Phosphorylation regulates the Atg9 interaction with Atg23 and Atg27 (Feng et al. 2016).  Atg27 is required for Atg9 cycling, and shuttles between the pre-autophagosomal structure, mitochondria, and the Golgi complex (Yen et al. 2007). Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). Matoba et al. 2020 reported that yeast and human Atg9 are lipid scramblases that translocate phospholipids between outer and inner leaflets of liposomes in vitro. Cryo-EM of fission yeast Atg9 revealed a homotrimer, with two connected pores forming a path between the two membrane leaflets: one pore, located at a protomer, opens laterally to the cytoplasmic leaflet; the other, at the trimer center, traverses the membrane vertically. Mutation of residues lining the pores impaired IM expansion and autophagy activity in yeast and abolished Atg9's ability to transport phospholipids between liposome leaflets. Thus, phospholipids delivered by Atg2 are translocated from the cytoplasmic to the luminal leaflet by Atg9, thereby driving autophagosomal membrane expansion. Guardia et al. 2020 solved a high-resolution cryoEM structure of the ubiquitously expressed human ATG9A isoform. ATG9A is a domain-swapped homotrimer with a unique fold, and has an internal network of branched cavities. The functional importance of the cavity-lining residues which could serve as conduits for transport of hydrophilic moieties, such as lipid headgroups, across the bilayer has been suggested (Guardia et al. 2020).

Autophagy-related protein complex of Saccharomyces cerevisiae
Atg9 (997 aas; 6TMSs) (Q12142) (homologous to Q5ANC9 below)
Atg11 (1178 aas; 0TMSs) (Q12527)
Atg23 (453 aas; 0 TMSs) (Q06671)
Atg27 (271 aas; ≤ 2 TMSs) (P46987)
Atg1 (897 aas; ≤ 2 TMSs) (P53104)
Atg2 (1592 aas; ≤ 2 TMSs) (P53855)
Atg13 (738 aas; ≤ 2 TMSs) (Q06628)
Atg18 (500 aas; ≤ 2 TMSs) (P43601)
Atg9 (528 aas) (Q5ANC9) (homologous to Q12142 above)
Atg22 (528 aas; 12 TMSs) (P25568) This protein is a member of the MFS and also has TC# 2.A.1.24.1.

The autophagy protein complex.  The molecular mechanisms of autophagy have been reviewed (Hurley and Young 2017; Dupont et al. 2017). Autophagy is related to apoptosis and autoimmunity (Song et al. 2017; Wu and Adamopoulos 2017).  It is an intracellular degradation process carried out by a double-membrane organelle, termed the autophagosome (Molino et al. 2017). Three proteins (TM9SF1 (TC#8.A.68.1.13), TMEM166 (listed here) and TMEM74 (TC# 9.B.189.2.1)) regulate autophagosome formation (He et al. 2009). The generation of Atg9 vesicles from a Rab11-positive reservoir is tightly controlled by the Bif-1-DNM2 membrane fission machinery in response to cellular demand for autophagy.

    Autophagy involves capture of cytoplasmic materials into double-membraned autophagosomes that subsequently fuse with lysosomes for degradation of the materials by lysosomal hydrolases. The cryoelectron microscopy structure of the human ATG9A isoform at 2.9-Å resolution has been solved (Guardia et al. 2020). The structure reveals a fold with a homotrimeric domain-swapped architecture, multiple membrane spans, and a network of branched cavities, consistent with ATG9A being a membrane transporter. Mutational analyses support a role for the cavities in the function of ATG9A. Structure-guided molecular simulations predict that ATG9A causes membrane bending, explaining the localization of this protein to small vesicles and highly curved edges of growing autophagosomes (Guardia et al. 2020).

Autophagosomes form de novo but how is poorly understood. Particularly enigmatic are autophagy-related protein 9 (Atg9)-containing vesicles that are required for autophagy machinery assembly but do not supply the bulk of the autophagosomal membrane. Sawa-Makarska et al. 2020 reconstituted autophagosome nucleation using recombinant components from yeast. They found that Atg9 proteoliposomes first recruited the phosphatidylinositol 3-phosphate kinase complex, followed by Atg21, the Atg2-Atg18 lipid transfer complex, and the E3-like Atg12-Atg5-Atg16 complex, which promoted Atg8 lipidation. They found that Atg2 could transfer lipids for Atg8 lipidation. In selective autophagy, these reactions could potentially be coupled to cargo via Atg19-Atg11-Atg9 interactions. They proposed that Atg9 vesicles form seeds that establish membrane contact sites to initiate lipid transfer from compartments such as the endoplasmic reticulum (Sawa-Makarska et al. 2020).

The autophagy protein complex of Homo sapiens
ATG14 of 492 aas (Q6ZNE5)
ATG7 of 703 aas (O95352)
ATG4B of 393 aas (Q9Y4P1)
ATG9A of 839 aas (Q7Z3C6)
ATG16L1 of 607 aas (Q676U5)
ATG13 of 517 aas (O75143)
ATG4D of 474 aas (Q86TL0)
ATG3 of 314 aas (Q9NT62)
ATG12 of 140 aas (O94817)
ATG101 of 218 aas (Q9BSB4)
ATG2 of 1,938 aas (Q2TAZ0)
ATG9B of 924 aas (Q674R7)
ATG2B of 2078 aas (Q96BY7)
ATG16L2 of 619 aas (Q8NAA4)
ATG5 of 275 aas (A9UGY9)

Plant autophagy protein complex.  This complex plays roles in development and stress responses (Lv et al. 2014).  Autophagic regulators and receptors have been identified (Zeng et al. 2016).  Autophagy may play a role in sexual reproduction (Kurusu and Kuchitsu 2017).

Autophagy complex of Arabidopsis thaliana (Mouse-ear cress)
ATG18A of 425 aas (Q93VB2)
ATG6 of 517 aas (Q9M367)
ATG8A of 137 aas (A8MS84)
ATG7 of 697 aas (Q94CD5)
ATG11 of 1,148 aas (Q9SUG7)
ATG10 of 225 aas (Q8VZ52)
ATG1A of 626 aas (Q94C95)
ATG5 of 337 aas (Q9FFI2)
ATG4B of 477 aas (Q9M1Y0)
ATG9 of 866 aas (Q8RUS5)
ATG3 of 313 aas (Q0WWQ1)
ATG13A of 603 aas (Q9SCK0)
ATG2 of 1,892 aas (F8S296)
ATG12A of 96 aas (Q8S924)
ATG1C of 733 aas (F4IRW0)