Structure
Volume 30, Issue 9, 1 September 2022, Pages 1340-1353.e3
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Article
Structural basis for tunable affinity and specificity of LxCxE-dependent protein interactions with the retinoblastoma protein family

https://doi.org/10.1016/j.str.2022.05.019Get rights and content
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Highlights

  • Binding data reveal a wide range of affinities of LxCxE motifs for Rb proteins

  • X-ray structures explain the importance of residues outside the core motif

  • Sequence differences in Rb and p107 at the LxCxE-binding site confer specificity

Summary

The retinoblastoma protein (Rb) and its homologs p107 and p130 are critical regulators of gene expression during the cell cycle and are commonly inactivated in cancer. Rb proteins use their “pocket domain” to bind an LxCxE sequence motif in other proteins, many of which function with Rb proteins to co-regulate transcription. Here, we present binding data and crystal structures of the p107 pocket domain in complex with LxCxE peptides from the transcriptional co-repressor proteins HDAC1, ARID4A, and EID1. Our results explain why Rb and p107 have weaker affinity for cellular LxCxE proteins compared with the E7 protein from human papillomavirus, which has been used as the primary model for understanding LxCxE motif interactions. Our structural and mutagenesis data also identify and explain differences in Rb and p107 affinities for some LxCxE-containing sequences. Our study provides new insights into how Rb proteins bind their cell partners with varying affinity and specificity.

Keywords

cell-cycle control
gene regulation
protein-protein interactions
short linear motif
tumor suppressor
Rb protein
viral oncogene
p107 protein

Data and code availability

X-ray diffraction data have been deposited in the Protein Data Bank and are publicly available as of the date of publication. Accession numbers are listed in Table 1 and the key resources table. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Lead contact