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 heterotrimeric complex with the pseudokinase STRADα, and the scaffolding protein MO25. This complex is essential for both proper kinase activity and proper localization. [6], [7]
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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.
STRADα
The WEF motif (aa 429-431) on the C-terminus of STRADα interacts with the C-terminus of MO25.
References
- ↑ 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
- ↑ 10.1001/jamaoncol.2021.4932
- ↑ 10.1091/mbc.E15-08-0569.
- ↑ 10.1038/sj.emboj.7600110
- ↑ 10.1074/jbc.M112.444620
- ↑ 10.1038/sj.emboj.7600110
- ↑ 10.1093/emboj/cdg490
