This article focuses on mTORC2, a protein kinase complex critical for diverse cellular functions, including growth, metabolism, and proliferation, whose dysregulation is implicated in various diseases like cancer. The authors aimed to determine the structural basis for how mTORC2 selectively recognizes and phosphorylates its substrates, particularly Akt, a crucial signaling protein. Using a combination of cryo-electron microscopy (cryo-EM), chemical semisynthesis, and cross-linking mass spectrometry, the study details two key structural interfaces between Akt and the mTORC2 subunit mSin1, showing that the recognition relies on the Akt protein's three-dimensional structure, not merely its linear sequence. These findings clarify the molecular mechanism of mTORC2's high substrate specificity and provide a foundation for designing selective mTORC2 inhibitors to improve the clinical utility of current treatments.

References:

• Taylor M S, Chen M, Hancock M, et al. Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2[J]. Science, 2025: eadv7111.