2ky6

Structure of ARC92VBD/MED25ACIDStructure of ARC92VBD/MED25ACID

Structural highlights

2ky6 is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	MED25, ACID1, ARC92, PTOV2, TCBAP0758 (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[MED25_HUMAN] Charcot-Marie-Tooth disease type 2B2. The disease is caused by mutations affecting the gene represented in this entry.^[1]

Function

[MED25_HUMAN] Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for RARA/RXRA-mediated transcription.^[2] ^[3] ^[4]

Publication Abstract from PubMed

The human Mediator coactivator complex interacts with many transcriptional activators and facilitates recruitment of RNA polymerase II to promote target gene transcription. The MED25 subunit is a critical target of the potent herpes simplex 1 viral transcriptional activator VP16. Here we determine the solution structure of the MED25 VP16-binding domain (VBD) and define its binding site for the N-terminal portion of the VP16 transactivation domain (TADn). A hydrophobic furrow, formed by a beta-barrel and two alpha-helices in MED25 VBD, interacts tightly with VP16 TADn. Mutations in this furrow prevent binding of VP16 TAD to MED25 VBD and interfere with the ability of overexpressed MED25 VBD to inhibit VP16-dependent transcriptional activation in vivo. This detailed molecular understanding of transactivation by the benchmark activator VP16 could provide important insights into viral and cellular gene activation mechanisms.

Structure of the VP16 transactivator target in the Mediator.,Milbradt AG, Kulkarni M, Yi T, Takeuchi K, Sun ZY, Luna RE, Selenko P, Naar AM, Wagner G Nat Struct Mol Biol. 2011 Apr;18(4):410-5. Epub 2011 Mar 6. PMID:21378963^[5]

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

References

↑ Leal A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, Morera B, Del Valle G, Lupski JR, Ekici A, Pasutto F, Endele S, Barrantes R, Berghoff C, Berghoff M, Neundorfer B, Heuss D, Dorn T, Young P, Santolin L, Uhlmann T, Meisterernst M, Sereda MW, Stassart RM, Meyer zu Horste G, Nave KA, Reis A, Rautenstrauss B. Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models. Neurogenetics. 2009 Oct;10(4):275-87. doi: 10.1007/s10048-009-0183-3. Epub 2009, Mar 17. PMID:19290556 doi:http://dx.doi.org/10.1007/s10048-009-0183-3
↑ Mittler G, Stuhler T, Santolin L, Uhlmann T, Kremmer E, Lottspeich F, Berti L, Meisterernst M. A novel docking site on Mediator is critical for activation by VP16 in mammalian cells. EMBO J. 2003 Dec 15;22(24):6494-504. PMID:14657022 doi:http://dx.doi.org/10.1093/emboj/cdg619
↑ Yang F, DeBeaumont R, Zhou S, Naar AM. The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2339-44. PMID:14983011
↑ Lee HK, Park UH, Kim EJ, Um SJ. MED25 is distinct from TRAP220/MED1 in cooperating with CBP for retinoid receptor activation. EMBO J. 2007 Aug 8;26(15):3545-57. Epub 2007 Jul 19. PMID:17641689 doi:http://dx.doi.org/7601797
↑ Milbradt AG, Kulkarni M, Yi T, Takeuchi K, Sun ZY, Luna RE, Selenko P, Naar AM, Wagner G. Structure of the VP16 transactivator target in the Mediator. Nat Struct Mol Biol. 2011 Apr;18(4):410-5. Epub 2011 Mar 6. PMID:21378963 doi:10.1038/nsmb.1999

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OCA

[1] Leal A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, Morera B, Del Valle G, Lupski JR, Ekici A, Pasutto F, Endele S, Barrantes R, Berghoff C, Berghoff M, Neundorfer B, Heuss D, Dorn T, Young P, Santolin L, Uhlmann T, Meisterernst M, Sereda MW, Stassart RM, Meyer zu Horste G, Nave KA, Reis A, Rautenstrauss B. Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models. Neurogenetics. 2009 Oct;10(4):275-87. doi: 10.1007/s10048-009-0183-3. Epub 2009, Mar 17. PMID:19290556 doi:http://dx.doi.org/10.1007/s10048-009-0183-3

[2] Mittler G, Stuhler T, Santolin L, Uhlmann T, Kremmer E, Lottspeich F, Berti L, Meisterernst M. A novel docking site on Mediator is critical for activation by VP16 in mammalian cells. EMBO J. 2003 Dec 15;22(24):6494-504. PMID:14657022 doi:http://dx.doi.org/10.1093/emboj/cdg619

[3] Yang F, DeBeaumont R, Zhou S, Naar AM. The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2339-44. PMID:14983011

[4] Lee HK, Park UH, Kim EJ, Um SJ. MED25 is distinct from TRAP220/MED1 in cooperating with CBP for retinoid receptor activation. EMBO J. 2007 Aug 8;26(15):3545-57. Epub 2007 Jul 19. PMID:17641689 doi:http://dx.doi.org/7601797

[5] Milbradt AG, Kulkarni M, Yi T, Takeuchi K, Sun ZY, Luna RE, Selenko P, Naar AM, Wagner G. Structure of the VP16 transactivator target in the Mediator. Nat Struct Mol Biol. 2011 Apr;18(4):410-5. Epub 2011 Mar 6. PMID:21378963 doi:10.1038/nsmb.1999

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