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Chittaranjan Das

Professor Chittaranjan  DasAssistant Professor—Biochemistry
Email: cdas@purdue.edu
Phone: 765-494-5478
Office: BRWN 3185

For Professor Das's individual Home Page click here.

The main focus of our lab is to understand the functional role deubiquitinating enzymes (deubiquitinases or DUBs) in cellular pathways, particularly the ones implicated in neurodegeneration (gradual loss of neurons), such as Alzheimerís disease (AD) and Parkinsonís disease (PD). A wide variety of biological processes are controlled by the reversible, post-translational modification of proteins by the covalent attachment of ubiquitin, a highly conserved 76-residue eukaryotic polypeptide. Ubiquitination can be thought of as the starting event of a signaling cascade (ubiquitin signaling) that is eventually terminated by the hydrolytic removal of the ubiquitin tag by a DUB. A survey of human genome reveals the presence of about 90 DUBs, suggesting their involvement in a wide variety of biochemical pathways. Our approach to studying DUBs is based on the combined application of a number of tools that include chemical synthesis of small molecule probes, X-ray crystallography, and mass spectrometry-based proteomics.

Structure of UCHL1 determined by X-ray crystallography suggests that the enzyme can adopt two states, an inactive state (in which the catalytic residues are misaligned, shown on the left) and a putative active state- in which the residues are brought into alignment by interaction of the protein with unknown cofactors. A proposed method for identification of cofactors of UCHL1 via activity-based purification from whole-cell extracts (right).

Currently, we are investigating the normal function of the neuronal DUB ubiquitin C-terminal hydrolase L1 (UCHL1)- a PD-associated, neuron-specific protein of unknown physiological function. Our efforts in this direction are aimed at developing cell-permeable small molecule inhibitors of UCHL1 that can be used to probe its function (both normal and disease-associated), determining its binding partners by affinity based purification from whole-cell extracts, and defining the molecular basis of how a naturally occurring variant of this enzyme- in which Ser at the position 18 is substituted by Tyr (called the S18Y polymorph)- provides protection from Parkinsonís disease (PD). In addition to UCHL1, we are also conducting structural and mechanistic investigations of other related enzymes thought to be involved in fundamental biochemical processes such as DNA repair, histone modification, and endocytosis of plasma membrane proteins.

Education

Ph.D. Indian Institute of Science (2001); Postdoctoral fellow (2001-2006) Harvard Medical School and Brandeis University.

Recognitions

  • Senior Research Fellowship, University Grants Commission, India , 1996-2001

Selected Publications

  • Davies CW, Chaney J, Korbel, G, Ringe, D, Ploegh, H, Petsko GA and Das C*, The co-crystal Structure of Ubiquitin Carboxy-terminal hydrolase L1 (UCHL1) with a tripeptide fluoromethyl ketone (Z-VAE(OMe)-FMK). Bioorganic and Medicinal Chemistry Letters 2012 , in press, .
  • Davies CW, Paul LN, Kim M and Das C*, Structural and Thermodynamic Comparison of the Catalytic Domain of AMSH and AMSH-LP: Nearly Identical Fold but Different Stability. Journal of Molecular Biology 2011 , 413, 416-29.
  • Andersson FI, McMorran L, Werrell EF, Crone WJ, Das C, Hsu SD and Jackson SE, The Effect of Parkinsonís Disease Associated Mutations on the Stability, Structure and Dynamics of the Deubiquitinating Enzyme UCH-L1. Journal of Molecular Biology 2011 , 407, 261-271.
  • Boudreaux, D. A.;Maiti, T. K.;Davies, C. W.;Das, C., Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation. Proceedings of the National Academy of Sciences of 2010 , 107, 20 9117-9122.
More Publications

Paul Shepson, Head
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