| Autor: |
Aljedani SS; Biological and Environmental Science and Engineering Division, Computational Biology Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal 2395-56900, Kingdom of Saudi Arabia., Aldehaiman A; Biological and Environmental Science and Engineering Division, Computational Biology Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal 2395-56900, Kingdom of Saudi Arabia., Sandholu A; Biological and Environmental Science and Engineering Division, Computational Biology Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal 2395-56900, Kingdom of Saudi Arabia., Alharbi S; Biological and Environmental Science and Engineering Division, Computational Biology Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal 2395-56900, Kingdom of Saudi Arabia., Mak VCY; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Wu H; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA., Lugari A; CRCM, CNRS, INSERM, Institut Paoli-Calmettes, Aix-Marseille University, 13009 Marseille, France., Jaremko M; Biological and Environmental Science and Engineering Division, Computational Biology Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal 2395-56900, Kingdom of Saudi Arabia., Morelli X; CRCM, CNRS, INSERM, Institut Paoli-Calmettes, Aix-Marseille University, 13009 Marseille, France., Backer JW; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA., Ladbury JE; School of Molecular and Cellular Biology, and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT., Nowakowski M; Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland., Cheung LWT; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Arold ST; Biological and Environmental Science and Engineering Division, Computational Biology Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal 2395-56900, Kingdom of Saudi Arabia. |
| Abstrakt: |
The phosphoinositide-3 kinase (PI3K), a heterodimeric enzyme, plays a pivotal role in cellular metabolism and survival. Its deregulation is associated with major human diseases, particularly cancer. The p85 regulatory subunit of PI3K binds to the catalytic p110 subunit via its C-terminal domains, stabilising it in an inhibited state. Certain Src homology 3 (SH3) domains can activate p110 by binding to the proline-rich (PR) 1 motif located at the N-terminus of p85. However, the mechanism by which this N-terminal interaction activates the C-terminally bound p110 remains elusive. Moreover, the intrinsically poor ligand selectivity of SH3 domains raises the question of how they can control PI3K. Combining structural, biophysical, and functional methods, we demonstrate that the answers to both these unknown issues are linked: PI3K-activating SH3 domains engage in additional "tertiary" interactions with the C-terminal domains of p85, thereby relieving their inhibition of p110. SH3 domains lacking these tertiary interactions may still bind to p85 but cannot activate PI3K. Thus, p85 uses a functional selection mechanism that precludes nonspecific activation rather than nonspecific binding. This separation of binding and activation may provide a general mechanism for how biological activities can be controlled by promiscuous protein-protein interaction domains. |
