User:Peyton Jenkins/Sandbox 1

Relevance and Disease

Lung cancer is the leading cause of cancer related death worldwide. In the United States alone, over 120,000 deaths were caused by lung cancer in 2024^[1]. Non small cell lung cancer make up approximately 84% of all lung cancer cases, and of these lung adenocarcinoma accounts for about 65%^[2]. In lung adenocarcinoma, STK11 is the third most commonly mutated gene, behind only KRAS and p53^[3]. STK11 is a master kinase, signalling upstream of AMPK family kinases, p53, and FAK, to regulate processes like anoikis, adhesion, growth, metabolism, and survival^{[4], [5]}. STK11 exists in a with the pseudokinase STRADα, and the scaffolding protein MO25. This complex is essential for both proper kinase activity and proper localization. ^{[6], [7]}

Germline mutations in STK11

Structural Highlights

STK11

STK11 can be broken down into 3 domains. An N-terminal domain (aa 1-42), kinase domain (aa 43-347), and a C-terminal domain (aa 348-433). The activation loop of STK11 is located from residues ~202-212. Within the activation loop is P204, which interacts with a hydrophobic pocket on MO25, which is necessary to stabilize the active conformation. D98 forms a salt bridge with K78, further stabilizing the active site. R74 hydrogen bonds with Q251 of STRADα to stabilize the interaction between the two proteins. The β2-β3 loop and β7-β8 sheets of STK11 also interact with STRADα. In the β2-β3 loop R74 hydrogen bonds with Q251 of STRADα. In this structure STK11 is bound to an ATP analogue, by K78 and D98.

STRADα

STRAD alpha is composed of 2 domains, an N-terminal domain (aa 1-58) and pseudokinase domain (aa 59-347). STRADα is termed a pseudokinase because it shares structural features, such as a p+1 loop and αG helix, with other kinases, but lacks catalytic activity. STRADα binds STK11 through its pseudokinase domain, with the activation loop interacting with the the β2-β3 loop and β7-β8 sheets of STK11. The αC of STRADα interacts with the surface of MO25, further stabilizing the interaction between proteins. Additionally there is a WEF motif (aa 429-431) on the C-terminus of STRADα interacting with the C-terminus of MO25.

MO25

MO25 is a repeat of α-helices spanning the entire length of the protein. Residues R240 and F243 interact with the A205 and A206 of the STK11 activation loop. This is not required for MO25 and STK11 binding, however mutating R240 and F243 resulted in a catalytically inactive complex, thus these residues are essential to orient and stabilize the active conformation of STK11.

References

1. ↑ https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf
2. ↑ 10.1001/jamaoncol.2021.4932
3. ↑ 10.1091/mbc.E15-08-0569.
4. ↑ 10.1038/sj.emboj.7600110
5. ↑ 10.1074/jbc.M112.444620
6. ↑ 10.1038/sj.emboj.7600110
7. ↑ 10.1093/emboj/cdg490