Suchergebnisse

16 páginas, 7 figuras, 2 tablas. Coordinates and structure factors have been deposited in the Protein Data Bank under accession code 6H48, 6H4B, 6H49, 6H4C. ; Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper phage, SaPIs are de-repressed by specific interactions of phage proteins with Stl. SaPIs have evolved a fascinating mechanism to ensure their promiscuous transfer by targeting structurally unrelated proteins performing identically conserved functions for the phage. Here we decipher the molecular mechanism of this elegant strategy by determining the structure of SaPIbov1 Stl alone and in complex with two structurally unrelated dUTPases from different S. aureus phages. Remarkably, SaPIbov1 Stl has evolved different domains implicated in DNA and partner recognition specificity. This work presents the solved structure of a SaPI repressor protein and the discovery of a modular repressor that acquires multispecificity through domain recruiting. Our results establish the mechanism that allows widespread dissemination of SaPIs in nature. ; This work was supported by grant BIO2016-78571-P from the Ministerio de Economia y Competitividad (Spain) and grant Prometeo II/2014/029 from Valencian Government (Spain) to A.M., and grants MR/M003876/1 and MR/S00940X/1 from the Medical Research Council (UK), BB/N002873/1 and BB/S003835/1 from the Biotechnology and Biological Sciences Research Council (BBSRC, UK), Wellcome Trust 201531/Z/16/Z, and ERC-ADG-2014 Proposal no. 670932 Dut-signal from EU to J.R.P. C.A. and J.R.C were supported by FPI BES-2014-068617 and FPU13/02880 predoctoral fellowships respectively. X-ray diffraction data collection was supported by Diamond Light Source block allocation group (BAG) Proposal MX14739 and MX16258 and Spanish Synchrotron Radiation Facility ALBA Proposal 2016071762 and 2017072262. J.R.P. is thankful to the Royal Society and the Wolfson Foundation for providing him support through a Royal Society Wolfson Fellowship. ; Peer reviewed

The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer. ; This work was supported by IRB, ICREA (X.S.), Obra Social "la Caixa" (E.D.M., E.S., and X.S.), MINECO (BIO2012-31043 and BIO2015-70092-R to X.S., BIO2014-53095-P to G.D.F.), Marató de TV3 (102030 to X.S. and 102031 to E.E.-P), the COFUND program of the European Commission (C.D.S.), the European Research Council (CONCERT, contract number 648201 to X.S.), the Ramón y Cajal program of MICINN (RYC-2011-07873 to C.W.B.), the Serra Hunter Program (E.E.-P.), AGAUR (SGR-2014-56RR14 to E.E.-P), and FEDER (G.D.F.). I.H. was supported by funding from the Chief Scientist's Office of the Scottish Government (ETM-258, ETM-382). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain).