Inter-domain flexibility in F-Box proteins revealed by integrative modeling
- 1The Hebrew University of Jerusalem
Abstract
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, their potential conformational dynamics remain poorly understood. Here, we employ an integrative modeling approach combining cryo-EM structures, cross-linking mass spectrometry (XL-MS), and deep learning-based conformational ensemble prediction to profile the accessible conformations of F-box proteins. Our analyses reveal a significant inter-domain flexibility in FBXL2 and FBXL17 that enables sampling of a broad range of conformations within assembled SCF and CSN-SCF complexes. By contrast, other F-box proteins, including FBXL1 and FBXO22, exhibit intrinsic flexibility but are restricted to a considerably narrower conformational landscape. Together, our work highlights inter-domain plasticity as a tunable architectural feature of F-box proteins, which may shape their functional versatility within SCF complexes.
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BibTeX
@misc{shor2026interdomain,
title = {{Inter-domain flexibility in F-Box proteins revealed by integrative modeling}},
author = {B. Shor and F. Jiao and H. Shi and H. Mao and C. Yu and M. Braitbard and L. Huang and N. Zheng and D. Schneidman-Duhovny},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.07.764542},
url = {https://www.biorxiv.org/content/10.64898/2026.11.07.764542v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Inter-domain flexibility in F-Box proteins revealed by integrative modeling
AU - B. Shor
AU - F. Jiao
AU - H. Shi
AU - H. Mao
AU - C. Yu
AU - M. Braitbard
AU - L. Huang
AU - N. Zheng
AU - D. Schneidman-Duhovny
PY - 2026
DA - 2026/11/07
PB - bioRxiv
DO - 10.64898/2026.11.07.764542
UR - https://www.biorxiv.org/content/10.64898/2026.11.07.764542v1
AB - 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, their potential conformational dynamics remain poorly understood. Here, we employ an integrative modeling approach combining cryo-EM structures, cross-linking mass spectrometry (XL-MS), and deep learning-based conformational ensemble prediction to profile the accessible conformations of F-box proteins. Our analyses reveal a significant inter-domain flexibility in FBXL2 and FBXL17 that enables sampling of a broad range of conformations within assembled SCF and CSN-SCF complexes. By contrast, other F-box proteins, including FBXL1 and FBXO22, exhibit intrinsic flexibility but are restricted to a considerably narrower conformational landscape. Together, our work highlights inter-domain plasticity as a tunable architectural feature of F-box proteins, which may shape their functional versatility within SCF complexes.
ER -