Evolution of AF6-RAS association and its implications in mixed-lineage leukemia

Smith, Matthew J.; Ottoni, Elizabeth; Ishiyama, Noboru; Goudreault, Marilyn; Haman, André; Meyer, Claus; Tucholska, Monika; Gasmi-Seabrook, Geneviève M.C.; Menezes, Serena; Laister, Rob C.; Minden, Mark D.; Marschalek, Rolf; Gingras, Anne‐Claude; Hoang, Trang; Ikura, Mitsuhiko

doi:10.1038/s41467-017-01326-5

Cited by 26 publications

(46 citation statements)

References 81 publications

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“…Multiple binding motifs on DOT1L would increase the DOT1L-binding affinity and enhance HOXA gene expression, an event reminiscent of the role of oligomerization proposed for MLL. Oligomerization of MLL via the self-association motifs of fusion partners has been reported to be important and sufficient to immortalize hematopoietic cells (Martin et al 2003;Smith et al 2017). Our DOT1L-AF10 data together with the previous DOT1L-AF9 studies revealed another mode of oligomerization of the MLL fusion proteins; i.e., heterodimerization between DOT1L and AF9 or AF10.…”

Section: A Role Of Zinc In the Leukemogenesissupporting

confidence: 68%

Structural and functional analysis of the DOT1L–AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis

Zhou¹,

Su²,

Xu³

et al. 2018

Genes Dev.

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The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A () gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10 and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L-AF10 complex and may be involved in the regulation of the gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against-rearranged leukemia.

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Section: A Role Of Zinc In the Leukemogenesissupporting

confidence: 68%

Structural and functional analysis of the DOT1L–AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis

Zhou¹,

Su²,

Xu³

et al. 2018

Genes Dev.

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“…We modeled complexes of RA1 and RA2 domains of AF6 with H-Ras and K-Ras. The interface of the modeled H-Ras/AFAD RA1 complex agrees with the experimentally determined structure and does not involve the allosteric lobe in the interface [59]. Interestingly, however, the interfaces of the modeled H-Ras/AFAD RA2, K-Ras4B/AFAD RA1 and K-Ras4B/ AFAD RA2 are largely composed of the allosteric lobe and further experimental analysis may provide more information about the functional outcome of this difference between the isoforms.…”

Section: Interactions Of Non-canonical Effectors With Ras Through Thesupporting

confidence: 72%

Ras-Efektör Etkileşimlerinin Yapısal Detaylarının Açığa Çıkarılması

Muratcioğlu

Özbabacan

2019

International Journal of Advances in Engineering and Pure Sciences

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Small membrane-associated Ras proteins mediate a wide range of cellular functions, such as cell proliferation, migration, survival, and differentiation; through binding and activating numerous effectors. Constitutively active mutant Ras proteins are detected in various types of human cancer and Ras community seeks approaches other than small-molecule Ras inhibitors; such as targeting the protein-protein interactions in the downstream Ras effector pathways and preventing its membrane localization. Although the most studied effectors of Ras, i.e. Raf, PI3K and RalGDS, bind Ras through the same site, they elicit opposing signaling pathways and thus, the temporal and spatial decision of the cell among them is critical. Elucidating the structural details of Ras-effector interactions can help us understand the cell decision and target the protein-protein interactions precisely. However, only a few crystal structures of Ras in complex with an effector are deposited in PDB. Here, the 3D structures of Ras/effector complexes were modeled with the PRISM algorithm and important binding sites as well as hot spot residues on Ras were identified. The effectors were also classified according to the binding regions on Ras, to determine the competitive pathways and the binding regions other than the "effector lobe". The modeled complexes reveal important information about the interfaces between Ras and its partners with the potential of guiding drug design studies to block oncogenic Ras signaling

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“…To bind RAS, the effector proteins use a ubiquitin (UB)-like fold: a RAS-binding domain (RBD) or a RAS-association domain (RA) [ 11 , 12 ]. While KRAS has not been co-crystallized with any of its effector proteins, distinct effector proteins have been resolved in complex with HRAS: RalGDS (PDB ID: 4G0N) [ 13 ], Raf-1 (PDB ID: 1LFD) [ 14 ], PI3Kγ (PDB ID: 1HE8) [ 15 ], PLCε (PDB ID: 2CL5) [ 16 ], RASSF5 (PDB ID: 3DDC) [ 17 ] and AF-6 (PDB ID: 6AMB) [ 18 ]. These effector proteins bind to HRAS on top of its switch regions: switch-I (residues 30–40) and switch-II (residues 58–72), and the binding conformation of HRAS is almost identical in all of the complexes ( S1A Fig ).…”

Section: Introductionmentioning

confidence: 99%

Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling

et al. 2018

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A mutated KRAS protein is frequently observed in human cancers. Traditionally, the oncogenic properties of KRAS missense mutants at position 12 (G12X) have been considered as equal. Here, by assessing the probabilities of occurrence of all KRAS G12X mutations and KRAS dynamics we show that this assumption does not hold true. Instead, our findings revealed an outstanding mutational bias. We conducted a thorough mutational analysis of KRAS G12X mutations and assessed to what extent the observed mutation frequencies follow a random distribution. Unique tissue-specific frequencies are displayed with specific mutations, especially with G12R, which cannot be explained by random probabilities. To clarify the underlying causes for the nonrandom probabilities, we conducted extensive atomistic molecular dynamics simulations (170 μs) to study the differences of G12X mutations on a molecular level. The simulations revealed an allosteric hydrophobic signaling network in KRAS, and that protein dynamics is altered among the G12X mutants and as such differs from the wild-type and is mutation-specific. The shift in long-timescale conformational dynamics was confirmed with Markov state modeling. A G12X mutation was found to modify KRAS dynamics in an allosteric way, which is especially manifested in the switch regions that are responsible for the effector protein binding. The findings provide a basis to understand better the oncogenic properties of KRAS G12X mutants and the consequences of the observed nonrandom frequencies of specific G12X mutations.

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Evolution of AF6-RAS association and its implications in mixed-lineage leukemia

Cited by 26 publications

References 81 publications

Structural and functional analysis of the DOT1L–AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis

Structural and functional analysis of the DOT1L–AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis

Ras-Efektör Etkileşimlerinin Yapısal Detaylarının Açığa Çıkarılması

Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling

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