Indraneel Ghosh

Indraneel Ghosh

Professor, BIO5 Institute
Professor, Chemistry and Biochemistry-Sci
Primary Department
Contact
(520) 621-6331

Work Summary

Work Summary
The broad objective of our research program in Bioorganic Chemistry and Chemical Biology is to construct protein therapeutics, protein mimetics, biomaterials, and biosensors. Our research at the University of Arizona is highly multidisciplinary and utilizes techniques in organic synthesis, biochemistry, molecular biology, and a host of physical characterization methods. Our research motto is simple: Unraveling mysteries and Enabling discoveries.

Research Interest

Research Interest
Professor Neel Ghosh, is the Emily Davis and Homer Weed Distinguished Professor ’08 at the University of Arizona. His laboratory is broadly interested in Chemical Biology and Protein Design and Engineering with a focus on developing new tools and methods for advancing human health. The laboratory has a particular current interest in understanding protein kinases and protein-protein interactions and designing new ways to inhibit them in human diseases. Neel Ghosh is also a co-founder and Chief Scientific Officer for Luceome Biotechnologies. Neel received his doctoral degree in 1998 while working with Professor Jean Chmielewski at Purdue University. His doctoral research focused on designing inhibitors of protein-protein interactions and self-replicating peptides. In 1998 he joined Professor Andrew Hamilton and Professor Lynne Regan’s laboratories at Yale University as a joint postdoctoral fellow. At Yale, he discovered the first conditional split-Green Fluorescent Protein, which has been used as a means for measuring protein-protein interactions by many laboratories and the methodology is sometimes called fluorescent protein complementation. In 2001, Neel Ghosh joined the Department of Chemistry and Biochemistry at the University of Arizona as an Assistant Professor and was promoted to Associate Professor and then to the Davis & Weed Chair and Full Professor in 2011. Keywords: Chemistry, Biochemistry, Biomedical Engineering, Cancer

Publications

Ghosh, I., Zhou, M., & Ghosh, I. -. (2004). Noncovalent multivalent assembly of jun peptides on a leucine zipper dendrimer displaying fos peptides. Organic letters, 6(20).

[reaction: see text] The synthesis and characterization of a new leucine-zipper dendrimer (LZD) is reported that displays four copies of the peptide corresponding to the coiled-coiled dimerization domain of Fos. Circular dichroism spectroscopy, fluorescence titration, and sedimentation equilibrium experiments demonstrate that Fos-LZD can noncovalently assemble four copies of the peptide corresponding to the coiled-coil domain of Jun. This work provides the basis for the future construction of noncovalently assembled multivalent protein assemblies displaying any protein of interest.

Gdalyahu, A., Ghosh, I., Levy, T., Sapir, T., Sapoznik, S., Fishler, Y., Azoulai, D., & Reiner, O. (2004). DCX, a new mediator of the JNK pathway. EMBO Journal, 23(4), 823-832.

PMID: 14765123;PMCID: PMC380994;Abstract:

Mutations in the X-linked gene DCX result in lissencephaly in males, and abnormal neuronal positioning in females, suggesting a role for this gene product during neuronal migration. In spite of several known protein interactions, the involvement of DCX in a signaling pathway is still elusive. Here we demonstrate that DCX is a substrate of JNK and interacts with both c-Jun N-terminal kinase (JNK) and JNK interacting protein (JIP). The localization of this signaling module in the developing brain suggests its functionality in migrating neurons. The localization of DCX at neurite tips is determined by its interaction with JIP and by the interaction of the latter with kinesin. DCX is phosphorylated by JNK in growth cones. DCX mutated in sites phosphorylated by JNK affected neurite outgrowth, and the velocity and relative pause time of migrating neurons. We hypothesize that during neuronal migration, there is a need to regulate molecular motors that are working in the cell in opposite directions: kinesin (a plus-end directed molecular motor) versus dynein (a minus-end directed molecular motor).

Stains, C. I., Mondal, K., & Ghosh, I. (2007). Molecules that target beta-amyloid. ChemMedChem, 2(12), 1674-1692.

PMID: 17952881;Abstract:

The devastating effects of Alzheimer's and related amyloidogenic diseases have inspired the synthesis and evaluation of numerous ligands to understand the molecular mechanism of the aggregation of the beta-amyloid peptide. Our review focuses on the current knowledge in this field with respect to molecules that have been demonstrated to interact with either oligomeric or fibrillar forms of the beta-amyloid peptide. We describe natural proteins, peptides, peptidomimetics, and small molecules that have been found to interfere with beta-amyloid aggregation. We also detail recent efforts in selecting molecules that target beta-amyloid isolated from antibody, protein, and peptide libraries. These new molecules will likely aid in deciphering the details of the aggregation pathway for the beta-amyloid peptide and provide reagents that may stabilize relevant oligomeric intermediates which likely have bearing on the pathophysiology of Alzheimer's disease. Moreover, the described anti-amyloid molecular toolbox will also provide an avenue for designing new diagnostic and therapeutic reagents. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

Shekhawat, S. S., & Ghosh, I. (2011). Split-protein systems: beyond binary protein-protein interactions.. Current opinion in chemical biology, 15(6), 789-797.

PMID: 22070901;Abstract:

It has been estimated that 650,000 protein-protein interactions exist in the human interactome (Stumpf et al., 2008), a subset of all possible macromolecular partnerships that dictate life. Thus there is a continued need for the development of sensitive and user-friendly methods for cataloguing biomacromolecules in complex environments and for detecting their interactions, modifications, and cellular location. Such methods also allow for establishing differences in the interactome between a normal and diseased cellular state and for quantifying the outcome of therapeutic intervention. A promising approach for deconvoluting the role of macromolecular partnerships is split-protein reassembly, also called protein fragment complementation. This approach relies on the appropriate fragmentation of protein reporters, such as the green fluorescent protein or firefly luciferase, which when attached to possible interacting partners can reassemble and regain function, thereby confirming the partnership. Split-protein methods have been effectively utilized for detecting protein-protein interactions in cell-free systems, Escherichia coli, yeast, mammalian cells, plants, and live animals. Herein, we present recent advances in engineering split-protein systems that allow for the rapid detection of ternary protein complexes, small molecule inhibitors, as well as a variety of macromolecules including nucleic acids, poly(ADP) ribose, and iron sulfur clusters. We also present advances that combine split-protein systems with chemical inducers of dimerization strategies that allow for regulating the activity of orthogonal split-proteases as well as aid in identifying enzyme inhibitors. Finally, we discuss autoinhibition strategies leading to turn-on sensors as well as future directions in split-protein methodology including possible therapeutic approaches. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ghosh, I., Porter, J. R., Lockwood, S. H., Segal, D. J., & Ghosh, I. -. (2010). Seeing genetic and epigenetic information without DNA denaturation using sequence-enabled reassembly (SEER). Methods in molecular biology (Clifton, N.J.), 649.

Virtually all methods for reading the sequence of bases in DNA rely on the ability to denature double-stranded DNA into single strands and then use Watson-Crick base-pairing rules to hybridize the strands with high specificity to another DNA primer or probe. However, nature frequently uses an alternative method, reading the sequence information directly from double-stranded DNA using sequence-specific DNA-binding proteins. Here we describe methods for the construction and testing of sequence probes based on engineered zinc finger DNA-binding proteins. Background is reduced using split-reporter molecules, and signal is amplified using enzymatic reporters. The resulting sequence-enabled reassembly (SEER) probes can be configured to detect DNA sequence (genetic) or DNA methylation (epigenetic) information.