Structure and function of the ULK1 complex in autophagy

Abstract

The ULK1 complex initiates autophagosome formation, linking cellular nutrient status to downstream events in autophagy. Recent work suggests that the ULK1 complex might also be activated in selective autophagy independent of nutrient or energy status. In this review we will discuss our current understanding of how the ULK1 complex is regulated by different signals, as well as how this complex then regulates other components of the autophagy machinery. Recently obtained structural data both on ULK1 and the orthologous yeast Atg1 complex are beginning to shed light on the higher-order organization of ULK1 complex. Ultimately, these insights might make it possible to understand how cargo organization and structure recruits and regulates ULK1 in selective autophagy initiation.

Figure 1. ULK1 in bulk and selective autophagy initiation

ULK1 is integral in initiating autophagy in response to various signals. The initiation of bulk autophagy is inhibited when ULK1 and ATG13 are phosphorylated by mTORC1. ULK1 phosphorylates the PI3KC3 complex subunit BECN1 and activates PI3KC3. AMPK stimulates autophagy through inactivation of mTORC1 and direct phosphorylation of ULK1. In some cases of selective autophagy, ULK1 has been shown to be activated or recruited to the vesicle-nucleation site through scaffolds including Huntingtin and Atg11, and adaptors such as optineurin, NDP52, and p62, which bind ubiquitinated substrates and LC3/Atg8 on the autophagosome membrane. It is likely that a great many other ULK1 substrates also have important roles in autophagy initiation and/or autophagosome maturation. By analogy to yeast, ULK1 is also likely to have essential non-catalytic roles in scaffolding autophagosome formation.

Figure 2. Structure of the ULK1 complex

Model of the ULK1 complex. The ULK1 (orange) kinase and EAT domains are conserved in mammals and yeast. ATG13 (green) and ATG101 (cyan) heterodimerize through their HORMA domains, and a newly discovered WF finger in ATG101 (cyan) may regulate interactions with partner proteins. On the basis of the yeast Atg17 structure, FIP200 (yellow) has been modeled as an elongated S-shaped scaffold. Crystal structures are shown for the human ATG13-ATG101 HORMA dimer (pdb: 5C50), with the WF finger residues shown as sticks; the human ATG13 LIR bound to LC3B (pdb: 3WAO), with the LIR shown in a stick model; the human ULK1 catalytic domain (pdb: 4WNP), bound to N~2~-(1H-benzimidazol-6-yl)-N~4~-(5-cyclobutyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine (“compound 6”), with the compound shown in a space-filling sphere model in the active site; yeast Atg17 (pdb: 4HPQ), with the Atg29 and Atg31 subunit omitted, shown as a stand-in for FIP200, whose structure is unknown; and the yeast Atg1 EAT domain-Atg13 MIM complex (pdb: 4P1N), as a model for the likely structure of the ULK1 EAT domain. ULK1 is likely a dimer in this complex; however, only the EAT domain of the second ULK1 molecule is shown for clarity. By analogy to the yeast Atg1 complex, a second ULK1 dimer (not shown) might associate with the opposite tip of FIP200, leading to a molecular chain. There are many phosphorylation sites in the complex, as listed in Table 1.