6mim

Crystal structure of AF9 YEATS domain Y78W mutant in complex with histone H3K9crCrystal structure of AF9 YEATS domain Y78W mutant in complex with histone H3K9cr

Structural highlights

6mim is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.525Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AF9_HUMAN A chromosomal aberration involving MLLT3 is associated with acute leukemias. Translocation t(9;11)(p22;q23) with KMT2A/MLL1. The result is a rogue activator protein.

Function

AF9_HUMAN Component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA.^[1] ^[2]

Publication Abstract from PubMed

The YEATS domain has been identified as a reader of histone acylation and more recently emerged as a promising anti-cancer therapeutic target. Here, we detail the structural mechanisms for pi-pi-pi stacking involving the YEATS domains of yeast Taf14 and human AF9 and acylated histone H3 peptides and explore DNA-binding activities of these domains. Taf14-YEATS selects for crotonyllysine, forming pi stacking with both the crotonyl amide and the alkene moiety, whereas AF9-YEATS exhibits comparable affinities to saturated and unsaturated acyllysines, engaging them through pi stacking with the acyl amide. Importantly, AF9-YEATS is capable of binding to DNA, whereas Taf14-YEATS is not. Using a structure-guided approach, we engineered a mutant of Taf14-YEATS that engages crotonyllysine through the aromatic-aliphatic-aromatic pi stacking and shows high selectivity for the crotonyl H3K9 modification. Our findings shed light on the molecular principles underlying recognition of acyllysine marks and reveal a previously unidentified DNA-binding activity of AF9-YEATS.

Structural insights into the pi-pi-pi stacking mechanism and DNA-binding activity of the YEATS domain.,Klein BJ, Vann KR, Andrews FH, Wang WW, Zhang J, Zhang Y, Beloglazkina AA, Mi W, Li Y, Li H, Shi X, Kutateladze AG, Strahl BD, Liu WR, Kutateladze TG Nat Commun. 2018 Nov 1;9(1):4574. doi: 10.1038/s41467-018-07072-6. PMID:30385749^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, Washburn MP, Conaway JW, Conaway RC, Shilatifard A. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010 Feb 12;37(3):429-37. doi: 10.1016/j.molcel.2010.01.026. PMID:20159561 doi:10.1016/j.molcel.2010.01.026
↑ He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, Krogan NJ, Alber T, Zhou Q. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010 May 14;38(3):428-38. doi: 10.1016/j.molcel.2010.04.013. PMID:20471948 doi:10.1016/j.molcel.2010.04.013
↑ Klein BJ, Vann KR, Andrews FH, Wang WW, Zhang J, Zhang Y, Beloglazkina AA, Mi W, Li Y, Li H, Shi X, Kutateladze AG, Strahl BD, Liu WR, Kutateladze TG. Structural insights into the pi-pi-pi stacking mechanism and DNA-binding activity of the YEATS domain. Nat Commun. 2018 Nov 1;9(1):4574. doi: 10.1038/s41467-018-07072-6. PMID:30385749 doi:http://dx.doi.org/10.1038/s41467-018-07072-6

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OCA

[1] Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, Washburn MP, Conaway JW, Conaway RC, Shilatifard A. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010 Feb 12;37(3):429-37. doi: 10.1016/j.molcel.2010.01.026. PMID:20159561 doi:10.1016/j.molcel.2010.01.026

[2] He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, Krogan NJ, Alber T, Zhou Q. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010 May 14;38(3):428-38. doi: 10.1016/j.molcel.2010.04.013. PMID:20471948 doi:10.1016/j.molcel.2010.04.013

[3] Klein BJ, Vann KR, Andrews FH, Wang WW, Zhang J, Zhang Y, Beloglazkina AA, Mi W, Li Y, Li H, Shi X, Kutateladze AG, Strahl BD, Liu WR, Kutateladze TG. Structural insights into the pi-pi-pi stacking mechanism and DNA-binding activity of the YEATS domain. Nat Commun. 2018 Nov 1;9(1):4574. doi: 10.1038/s41467-018-07072-6. PMID:30385749 doi:http://dx.doi.org/10.1038/s41467-018-07072-6

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[2]

[3]

6mim

Crystal structure of AF9 YEATS domain Y78W mutant in complex with histone H3K9crCrystal structure of AF9 YEATS domain Y78W mutant in complex with histone H3K9cr

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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6mim

Crystal structure of AF9 YEATS domain Y78W mutant in complex with histone H3K9crCrystal structure of AF9 YEATS domain Y78W mutant in complex with histone H3K9cr

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

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