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Ishwar Radhakrishnan

Ishwar Radhakrishnan

Professor
Molecular Biosciences
PhD, Columbia University

Email: i-radhakrishnan@northwestern.edu
Phone: (847) 467-1173
Fax: (847) 467-6489
Room: Cook 4135

 

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Research Interests

Structure and Biology of Macromolecular Complexes in Transcription Regulation

The Radhakrishnan lab is interested in the molecular mechanisms of transcription regulation, specifically, how transcription factors bind DNA and recruit coactivators thereby nucleating protein-protein interaction networks that extend to the transcription machinery, and how chromatin-modifying complexes read, interpret, and modify the histone code. We are asking these questions in the context of (i) cAMP signaling mediated by CREB and its coactivators and (ii) a cohort of related, yet functionally distinct, histone deacetylase (HDAC)-associated chromatin-modifying complexes. Separately, we are also developing software for analyzing experimentally-determined structures of protein-protein/nucleic acid complexes with the goal of automating the process of deciphering the ‘rules’ of macromolecular associations.

Molecular mechanisms of recruitment and assembly of Sin3/HDAC corepressor complexes in transcriptional repression
Multiprotein complexes containing chromatin-modifying enzymes play an important role in reading, interpreting, and altering the histone code thereby changing the transcriptional status of specific genetic loci. We are investigating how two functionally distinct forms of the Sin3/HDAC corepressor complex are recruited to specific sites on the genome, how these complexes are assembled, and what role(s) the constitutively-associated subunits of the complex play in effecting specific transcriptional outcomes. These questions bear significance, as not only have multiple components of these complexes been implicated in the genesis and progression of cancers, the key enzymatic components of this complex – the so-called HDACs – are proven targets of cancer therapy.

Phosphorylation-independent mechanism of transcriptional activation by CREB
The cyclic AMP responsive transcription factor CREB activates transcription via both phosphorylation-dependent and -independent mechanisms. Whereas the phosphorylation-dependent mechanism involving cyclic AMP dependent kinases relies on the recruitment of p300/CBP coactivators and is well characterized, phosphorylation-independent mechanisms of transcriptional activation are poorly understood. Since members of the CRTC/TORC family of coactivators have been recently implicated in the latter pathway, which regulates blood glucose levels during fasting and is relevant to the development of type 2 diabetes, we are seeking to clarify the molecular basis of these interactions with CREB and also with downstream effectors including coactivators and histone acetyltransferases. Since several CRTC/TORC family members are involved in chromosomal translocations that lead to certain cancers, we are also seeking to clarify the precise molecular roles of these aberrant proteins.

Methods for automated analysis of macromolecular complexes
We had previously developed a web application that detects stabilizing intermolecular interactions in macromolecular complexes from atomic coordinate data. The core software called MONSTER comprises a PERL wrapper that takes advantage of established software in the public domain to validate atomic coordinate files, identify interacting residues, and assign the nature of these interactions. The results are integrated and presented in an intuitive and interactive graphical format. Applications of MONSTER range from mining and validating experimentally-determined structures to guiding mutational analysis. We are presently expanding the scope of MONSTER to guide (i) automated sequence motif identification, (ii) molecular modeling of homologous complexes and (iii) developing a hierarchical classification scheme for macromolecular complexes. A version of the software is available at http://monster.northwestern.edu.

Selected Publications

Molecular Basis for the Mechanism of Constitutive CBP/p300 Coactivator Recruitment by CRTC1-MAML2 and Its Implications in cAMP Signaling. Clark MD, Kumar GS, Marcum R, Luo Q, Zhang Y, and Radhakrishnan I. Biochemistry. 2015 September 8;54(35):5439-5446.

Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex. Clark MD, Marcum R, Graveline R, Chan CW, Xie T, Chen Z, Ding Y, Zhang Y, Mondragón A, David G, and Radhakrishnan I. PNAS. 2015 July 14;112(28):E3669-E3678.

Structural Basis for Multi-specificity of MRG Domains. Xie T, Zmyslowski AM, Zhang Y, and Radhakrishnan I. Structure. 2015 June 2;23(6):1049-1057.

A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer. Kim J-Y, Banerjee T, Vinckevicius A, Luo Q, Parker JB, Baker MR, Radhakrishnan I, Wei J-J, Barish GD, and Chakravarti D. Molecular Cell. 2014 May 22;54(4):613-625.

Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2. Luo Q, Viste K, Urday-Zaa JC, Kumar GS, Tsai W-W, Talai A, Mayo KE, Montminy M, and Radhakrishnan I. PNAS. 2012 December 18;109(51):20865-20870.

Sequence Requirements for Combinatorial Recognition of Histone H3 by the MRG15 and Pf1 Subunits of the Rpd3S/Sin3S Corepressor Complex. Kumar GS, Chang W, Xie T, Patel A, Zhang Y, Wang GG, David G, and Radhakrishnan I. Journal of Molecular Biology. 2012 September 28;422(4):519-531.

Structural Basis for Molecular Interactions Involving MRG Domains: Implications in Chromatin Biology. Xie T, Graveline R, Kumar GS, Zhang Y, Krishnan A, David G, and Radhakrishnan I. Structure. 2012 January 11;20(1):151-160.

Structure of the 30-kDa Sin3-associated Protein (SAP30) in Complex with the Mammalian Sin3A Corepressor and Its Role in Nucleic Acid Binding. Xie T, He Y, Korkeamaki H, Zhang Y, Imhoff R, Lohi O, and Radhakrishnan I. Journal of Biological Chemistry. 2011 August 5;286(31):27814-27824.

Solution Structure of the mSin3A PAH2–Pf1 SID1 Complex: A Mad1/Mxd1-Like Interaction Disrupted by MRG15 in the Rpd3S/Sin3S Complex. Kumar GS, Xie T, Zhang Y, and Radhakrishnan I. Journal of Molecular Biology. 2011 May 20;408(5):987-1000.

Solution structure of a novel zinc finger motif in the SAP30 polypeptide of the Sin3 corepressor complex and its potential role in nucleic acid recognition. He Y, Imhoff R, Sahu A, and Radhakrishnan I. Nucleic Acids Research. 2009 April;37(7):2142-2152.

Conserved Themes in Target Recognition by the PAH1 and PAH2 Domains of the Sin3 Transcriptional Corepressor. Sahu SC, Swanson KA, Kang RS, Huang K, Brubaker K, Ratcliff K, and Radhakrishnan I. Journal of Molecular Biology. 2008 February 1;375(5):1444-1456.

View all publications by Ishwar Radhakrishnan listed in the National Library of Medicine (PubMed). Current and former IBiS students in blue.