Biophysical and Structural Characterization of Biological Macromolecules
Our research group explores complex biological problems associated with signal transduction and neurodegenerative diseases, including Alzheimer’s disease, ALS, and Parkinson’s disease. We are especially interested in understanding the interplay between protein dynamics and function.
Research
We characterize the structure-function interplay and conformational dynamics of biological macromolecules using a range of cutting-edge biophysical methods. Our primary research interests are:
Solution NMR spectroscopy.
Solution NMR elucidates the structures of biomolecules in their native environment. It is also unique in its ability to elucidate the range of motions that are exhibited by biomolecules. These motions provide vital information regarding ligand recognition, protein assembly, conformational dynamics, and other essential cellular processes.
Protein phase separation and amyloids.
Phase separation of proteins orchestrates a variety of cellular processes, and its dysregulation can lead to amyloid fibrils, which are often associated with proteinopathies. We want to understand the mechanistic underpinnings of these transitions. Additionally, we seek to understand the phenomenon of functional amyloids that perform essential physiological roles without succumbing to pathology.
Posttranslational modifications (PTMs).
PTMs are used to extend and diversify the signals encoded by a given protein. Some of the common PTMs include the introduction of a functional group (e.g., phosphorylation), covalent conjugation of peptides or proteins (e.g., ubiquitination), and proteolytic cleavage of the target protein. We are especially interested in proteolysis, tyrosine phosphorylation, and ubiquitination.
People
Publications
At UCSD
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27.Yu C., Nelson S. L., Meisl G., Ghirlando R., Deshmukh L. (2023) Phase separation and fibrillization of human annexin A7 are mediated by its proline-rich domain. Biochemistry. Epub ahead of print.
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26.Elias, R. D., Zhu, Y., Su, Q., Ghirlando, R., Zhang, J., Deshmukh, L. (2023) Reversible phase separation of ESCRT-protein ALIX through tyrosine phosphorylation. Sci Adv 9, eadg3913.
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25.Shihora, A., Elias, R. D., Hammond, J. A., Ghirlando, R., and Deshmukh, L. (2023) ALS variants of annexin A11's proline-rich domain impair its S100A6-mediated fibril dissolution. ACS Chem Neurosci 14, 2583-2589.
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24.Nelson S. L., Li Y., Chen Y., Deshmukh L. (2023) Avidity-based method for the efficient generation of monoubiquitinated recombinant proteins. J Am Chem Soc 145, 7748-7752.
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23.Elias, R. D., Ramaraju, B., and Deshmukh, L. (2021) Mechanistic roles of tyrosine phosphorylation in reversible amyloids, autoinhibition, and endosomal membrane association of ALIX. J Biol Chem, 297,101328.
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22. Quantitative NMR study of insulin-degrading enzyme using amyloid-β and HIV-1 p6 elucidates its chaperone activity. Biochemistry 60, 2519-2523.
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21. Elias, R. D., Ma, W., Ghirlando, R., Schwieters, C. D., Reddy, V. S., and Deshmukh, L. (2020) Proline-rich domain of human ALIX contains multiple TSG101-UEV interaction sites and forms phosphorylation-mediated reversible amyloids. Proc Natl Acad Sci U S A 117, 24274-24284.
Prior to UCSD - National Institutes of Health
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20. Inhibition of HIV maturation via selective unfolding and cross-linking of Gag polyprotein by a mercaptobenzamide acetylator. J Am Chem Soc 141, 8327-8338.
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19. Targeting a dark excited state of HIV-1 nucleocapsid by antiretroviral thioesters revealed by NMR spectroscopy. Angew Chem Int Ed Engl 57, 2687-2691.
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18. Binding kinetics and substrate selectivity in HIV-1 protease-Gag interactions probed at atomic resolution by chemical exchange NMR. Proc Natl Acad Sci U S A 114, E9855-E9862.
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17. Transient HIV-1 Gag-protease interactions revealed by paramagnetic NMR suggest origins of compensatory drug resistance mutations. Proc Natl Acad Sci U S A 113, 12456-12461.
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14. Conformation and dynamics of the Gag polyprotein of the human immunodeficiency virus 1 studied by NMR spectroscopy. Proc Natl Acad Sci U S A 112, 3374-3379.
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13. Investigation of the structure and dynamics of the capsid-spacer peptide 1-nucleocapsid fragment of the HIV-1 Gag polyprotein by solution NMR spectroscopy. Angew Chem Int Ed Engl 53, 1025-1028.
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12. Structure and dynamics of full-length HIV-1 capsid protein in solution. J Am Chem Soc 133, 16133-16147.
Prior to UCSD - University of Connecticut
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11. Skelemin association with alphaIIbbeta3 integrin: a structural model. Biochemistry 53, 6766-6775.
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9. Tyrosine phosphorylation as a conformational switch: A case study of integrin beta3 cytoplasmic tail. J Biol Chem 286, 40943-40953.
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7. Integrin beta3 phosphorylation dictates its complex with the Shc phosphotyrosine-binding (PTB) domain. J Biol Chem 285, 34875-34884.
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6. NMR solution structure of human cannabinoid receptor-1 helix 7/8 peptide: Candidate electrostatic interactions and microdomain formation. Biochem Biophys Res Commun 390, 441-446.
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5. Structural biology of human cannabinoid receptor-2 helix 6 in membrane-mimetic environments. Biochem Biophys Res Commun 384, 243-248.
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3. The solution structure of Bacillus anthracis dihydrofolate reductase yields insight into the analysis of structure-activity relationships for novel inhibitors. Biochemistry 48, 4100-4108 (*Authors contributed equally).
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1. Structural insight into the interaction between platelet integrin alphaIIbbeta3 and cytoskeletal protein skelemin. J Biol Chem 282, 32349-32356.
Contact
Contact information
Department of Chemistry and
Biochemistry
University of California San Diego
9500 Gilman Drive
La Jolla, CA 92093-0375
Office – NSB #3113
Lab – NSB #3108
Phone (office): (858)-246-3343
Phone (lab): (858)-246-3161
Email: