Inter-domain flexibility in F-Box proteins revealed by integrative modeling
F-box proteins, the substrate-recognition modules of the SCF (Skp1-Cul1-F-box) ubiquitin ligase complex, play a central role in targeted protein degradation by enabling the selective recruitment of diverse substrates. F-box proteins share a common architecture with a conserved anchor domain linked to the substrate-binding domain. Despite extensive structural characterization of F-box proteins,…
F-box proteins, essential components of the SCF ubiquitin ligase complex, are responsible for selectively recruiting substrates for targeted protein degradation. These proteins possess a common architecture consisting of an anchor domain connected to a substrate-binding domain. Although the structural characteristics of F-box proteins have been extensively studied, their potential conformational dynamics have not been thoroughly explored.
To investigate this, researchers utilized an integrative modeling approach that integrated cryo-EM structures, cross-linking mass spectrometry, and deep learning-based conformational ensemble prediction. This approach enabled the profiling of the accessible conformations of various F-box proteins. The analyses conducted revealed a significant inter-domain flexibility in FBXL2 and FBXL17, which allows these proteins to sample a wide range of conformations within the SCF and CSN-SCF complexes.
In contrast, other F-box proteins, such as FBXL1 and FBXO22, exhibit intrinsic flexibility but are restricted to a narrower conformational landscape. These findings highlight the importance of inter-domain plasticity as a tunable architectural feature of F-box proteins. This flexibility may play a crucial role in shaping their functional versatility within SCF complexes.
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