Molecular dynamics of the fusion oncoprotein EML4-ALK in lung cancer as revealed by high-speed AFM

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22837
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Kanazawa University
• Principal Investigator: HAN XUJUN 金沢大学, ナノ生命科学研究所, 特任助教 (30872163)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: ALK / EML4 / HS-AFM / fusion oncoprotein / lung cancer / structure

Outline of Final Research Achievements

Fusion oncoprotein EML4-ALK is one of the strong drive mutations in lung cancer. However, the overall structure remains unclear because the N-terminal region is an intrinsically disordered protein region (IDPR) whose structure is hard detectable by conventional tools. In this study, we have imaged the real-time structures of EML4-ALK in monomer, dimer, and trimer forms by using a high-speed atomic force microscope (HS-AFM). Interestingly, we found the dimer is more stable than the trimer and the ALK inhibitors can indirectly suppress the dimeric rates through the IDPR region distortion. This work clarified the structural profiles of IDPR in EML4-ALK fusions for the first time, and our data suggested new strategies against the cancers of EML4-ALK based on the overall structures.

Free Research Field

Cancer biology

Academic Significance and Societal Importance of the Research Achievements

This is the first dataset to describe the overall structures of the fusion oncoprotein EML4-ALK variants by HS-AFM, which greatly broadens our knowledge of this oncoprotein. As EML4-ALK is an important therapeutic target, this work would be important in both academic and societal implications.