ULK1


ULK1 is an enzyme that in humans is encoded by the ULK1 gene.
Unc-51 like autophagy activating kinase ' are two similar isoforms of an enzyme that in humans are encoded by the ULK1/2'' genes.ULK1#cite note-pmid9693035-5|ULK1#cite note-entrez-6| It is specifically a kinase that is involved with autophagy, particularly in response to amino acid withdrawal. Not many studies have been done comparing the two isoforms, but some differences have been recorded.

Function

Ulk1/2 is an important protein in autophagy for mammalian cells, and is homologous to ATG1 in yeast. It is part of the ULK1-complex, which is needed in early steps of autophagosome biogenesis. The ULK1 complex also consists of the FAK family kinase interacting protein of 200 kDa and the HORMA domain-containing proteins ATG13 and ATG101. ULK1, specifically, appears to be the most essential for autophagy and is activated under conditions of nutrient deprivation by several upstream signals which is followed by the initiation of autophagy. However, ULK1 and ULK2 show high functional redundancy; studies have shown that ULK2 can compensate for the loss of ULK1. Nutrient dependent autophagy is only fully inhibited if both ULK1 and ULK2 are knocked out.
ULK1 has many downstream phosphorylation targets to aid in this induction of the isolation membrane/ autophagosome. Recently, a mechanism for autophagy has been elucidated. Models have proposed that the active ULK1 directly phosphorylates Beclin-1 at Ser 14 and activates the pro-autophagy class III phosphoinositide 3-kinase, VPS34 complex, to promote autophagy induction and maturation.
Ulk1/2 is negatively regulated by mTORC1 activity, which is active during anabolic-type environmental cues. In contrast, Ulk1/2 is activated by AMPK activity from starvation signals.
Ulk1/2 may have critical roles beyond what ATG1 performs in yeast, including neural growth and development.

Interactions

When active, mTORC1 inhibits autophagy by phosphorylating both ULK1 and ATG13, which reduces the kinase activity of ULK1. Under starvation conditions, mTORC1 is inhibited and dissociates from ULK1 allowing it to become active. AMPK is activated when intracellular AMP increases which occurs under starvation conditions, which inactivates mTORC1, and thus directly activates ULK1. AMPK also directly phosphorylates ULK1 at multiple sites in the linker region between the kinase and C-terminal domains.
ULK1 can phosphorylate itself as well as ATG13 and RB1CC1, which are regulatory proteins; however, the direct substrate of ULK1 has not been identified although recent studies suggest it phosphorylates Beclin-1.
Upon proteotoxic stresses, ULK1 has been found to phosphorylate the adaptor protein p62, which increases the binding affinity of p62 for ubiquitin.
ULK1 has been shown to interact with Raptor, Beclin1, Class-III-PI3K, GABARAPL2,ULK1#cite note-pmid11146101-7| GABARAP,ULK1#cite note-pmid11146101-7|ULK1#cite note-pmid17353931-8| SYNGAP1ULK1#cite note-pmid15014045-9| and SDCBP.ULK1#cite note-pmid15014045-9|

Structure

ULK1 is a 112-kDa protein. It contains a N-terminal kinase domain, a serine-proline rich region, and a C-terminal interacting domain. The serine-proline rich region has been shown experimentally to be the site of phosphorylation by mTORC1 and AMPK—a negative and positive regulator of ULK1 activity, respectively. The C-terminal domain contains two microtubule-interacting and transport domains and acts as a scaffold which links ULK1, ATG13, and FIFP200 together to form a complex that is essential to initiate autophagy. Early autophagy targeting/tethering domains in the C-terminus are arranged as MIT domains consisting of two three-helix bundles. MIT domains also mediate interactions with membranes. The N-terminus contains a serine-threonine kinase domain. ULK1 also contains a large activation loop between the N and C terminus that is positively charged. This region may regulate kinase activity and play a role in recognizing different substrates. ULK1 and ULK2 share significant homology in both the C-terminal and N-terminal domains.

Related Diseases

Given ULK1's role in autophagy, many diseases such as cancer, neurodegenerative disorders, neurodevelopment disorders, and Crohn's disease could be attributed to any impairments in autophagy regulation.
In cancer specifically, ULK1 has become an attractive therapeutic target. Since autophagy acts as a cell survival trait for cells, it enables tumors to survive energy deprivation and other stresses such as chemotherapeutics. For that reason, inhibiting autophagy may prove to be beneficial. Thus, inhibitors have been targeted towards ULK1.