Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family

Liban, Tyler J.; Medina, Edgar M.; Tripathi, Sarvind; Sengupta, Satyaki; Henry, R. William; Buchler, Nicolas E.; Rubin, Seth M.

doi:10.1073/pnas.1619170114

Title: Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family

Journal Article · Mon Apr 24 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1619170114· OSTI ID:1373775

Liban, Tyler J. ^[1]; Medina, Edgar M. ^[2];

^[1]; Sengupta, Satyaki ^[3]; Henry, R. William ^[3];

^[2]; Rubin, Seth M. ^[1]

Univ. of California, Santa Cruz, CA (United States)
Duke Univ., Durham, NC (United States)
Michigan State Univ., East Lansing, MI (United States)

The retinoblastoma protein (Rb) and the homologous pocket proteins p107 and p130 negatively regulate cell proliferation by binding and inhibiting members of the E2F transcription factor family. Here, the structural features that distinguish Rb from other pocket proteins have been unclear but are critical for understanding their functional diversity and determining why Rb has unique tumor suppressor activities. We describe here important differences in how the Rb and p107 C-terminal domains (CTDs) associate with the coiled-coil and marked-box domains (CMs) of E2Fs. We find that although CTD–CM binding is conserved across protein families, Rb and p107 CTDs show clear preferences for different E2Fs. A crystal structure of the p107 CTD bound to E2F5 and its dimer partner DP1 reveals the molecular basis for pocket protein–E2F binding specificity and how cyclin-dependent kinases differentially regulate pocket proteins through CTD phosphorylation. Our structural and biochemical data together with phylogenetic analyses of Rb and E2F proteins support the conclusion that Rb evolved specific structural motifs that confer its unique capacity to bind with high affinity those E2Fs that are the most potent activators of the cell cycle.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Health

Grant/Contract Number:: AC02-06CH11357; R01CA132685

OSTI ID:: 1373775

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 19; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 23 works

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The putative tumour suppressor miR-1-3p modulates prostate cancer cell aggressiveness by repressing E2F5 and PFTK1 Li, Sen-Mao; Wu, Huan-Lei; Yu, Xiao Journal of Experimental & Clinical Cancer Research, Vol. 37, Issue 1 https://doi.org/10.1186/s13046-018-0895-z	journal	September 2018
Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes Fischer, Martin; Müller, Gerd A. Critical Reviews in Biochemistry and Molecular Biology, Vol. 52, Issue 6 https://doi.org/10.1080/10409238.2017.1360836	journal	August 2017
Non-canonical functions of the RB protein in cancer Dick, Frederick A.; Goodrich, David W.; Sage, Julien Nature Reviews Cancer, Vol. 18, Issue 7 https://doi.org/10.1038/s41568-018-0008-5	journal	April 2018
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Title: Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family

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