Lars Plate, Ph.D.

Assistant Professor

lars.plate@vanderbilt.edu

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Faculty Appointments
Assistant Professor of Chemistry Assistant Professor of Biological Sciences
Education
Ph.D., Molecular and Cell Biology, University of California, Berkeley, CaliforniaB.S., Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts
Research Description
The focus of the group is to define the dynamics and the coordination of protein interaction networks in diverse cellular processes. Towards this goal, we develop new mass spectrometry-based proteomics and chemical biology tools. Dynamic protein-protein interactions govern many molecular, cellular, and organismal processes and altered interactions are intricately linked to disease states. For instance, in cancer disparate protein-protein interactions occur in signal transduction pathways, protein folding diseases arise from aberrant engagement of protein folding pathways, and pathogenic infections take advantage of host-pathogen protein interactions that co-opt cellular pathways. Our goal is to understand how protein interactions in the pertinent biological processes have to be properly timed and coordinated. Defining the pathological consequences of mistimed and uncoordinated protein interactions on disease states will then guide the identification of new therapeutic strategies.

The research in our group leverages multidisciplinary approaches at the interface of Chemistry and Biology, ranging from protein biochemistry and enzymology, to microbiology, and cell biology as far as proteomics and drug discovery.

We currently work on three interrelated projects:

1) Dynamics of chaperone interactions with client proteins during folding and secretion
2) Hemeprotein proteostasis and dysregulation by stress and disease
3) Coordination of host pathogen protein-protein interactions during flavivirus infections

Research Keywords
Dynamics and coordination of protein interaction networks; proteostasis, protein folding, and protein quality control; host-virus protein interactions; chemical biology and proteomics tools; mass spectrometry; biochemistry; enzymology; microbiology
Publications
Grandjean JMD, Plate L, Morimoto RI, Bollong MJ, Powers ET, Wiseman RL. Deconvoluting Stress-Responsive Proteostasis Signaling Pathways for Pharmacologic Activation Using Targeted RNA Sequencing. ACS Chem. Biol [print-electronic]. 2019 Mar 3/13/2019; PMID: 30821953, DOI: 10.1021/acschembio.9b00134, ISSN: 1554-8937.

Blackwood EA, Azizi K, Thuerauf DJ, Paxman RJ, Plate L, Kelly JW, Wiseman RL, Glembotski CC. Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis. Nat Commun. 2019 Jan 1/14/2019; 10(1): 187. PMID: 30643122, PMCID: PMC6331617, PII: 10.1038/s41467-018-08129-2, DOI: 10.1038/s41467-018-08129-2, ISSN: 2041-1723.

Paxman R, Plate L, Blackwood EA, Glembotski C, Powers ET, Wiseman RL, Kelly JW. Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins. Elife. 2018 Aug 8/7/2018; 7: PMID: 30084354, PMCID: PMC6080950, PII: 37168, DOI: 10.7554/eLife.37168, ISSN: 2050-084X.

Kroeger H, Grimsey N, Paxman R, Chiang WC, Plate L, Jones Y, Shaw PX, Trejo J, Tsang SH, Powers E, Kelly JW, Wiseman RL, Lin JH. The unfolded protein response regulator ATF6 promotes mesodermal differentiation. Sci Signal. 2018 Feb 2/13/2018; 11(517): PMID: 29440509, PII: 11/517/eaan5785, DOI: 10.1126/scisignal.aan5785, ISSN: 1937-9145.

Mortenson DE, Brighty GJ, Plate L, Bare G, Chen W, Li S, Wang H, Cravatt BF, Forli S, Powers ET, Sharpless KB, Wilson IA, Kelly JW. "Inverse Drug Discovery" Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates. J. Am. Chem. Soc [print-electronic]. 2018 Jan 1/10/2018; 140(1): 200-10. PMID: 29265822, PMCID: PMC5762408, DOI: 10.1021/jacs.7b08366, ISSN: 1520-5126.

Schonhoft JD, Monteiro C, Plate L, Eisele YS, Kelly JM, Boland D, Parker CG, Cravatt BF, Teruya S, Helmke S, Maurer M, Berk J, Sekijima Y, Novais M, Coelho T, Powers ET, Kelly JW. Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients. Sci Transl Med. 2017 Sep 9/13/2017; 9(407): PMID: 28904227, PMCID: PMC5628019, PII: 9/407/eaam7621, DOI: 10.1126/scitranslmed.aam7621, ISSN: 1946-6242.

Chen KC, Qu S, Chowdhury S, Noxon IC, Schonhoft JD, Plate L, Powers ET, Kelly JW, Lander GC, Wiseman RL. The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer. EMBO J [print-electronic]. 2017 Aug 8/1/2017; 36(15): 2296-309. PMID: 28655754, PMCID: PMC5538767, PII: embj.201695616, DOI: 10.15252/embj.201695616, ISSN: 1460-2075.

Alvarez-Garcia O, Matsuzaki T, Olmer M, Plate L, Kelly JW, Lotz MK. Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis. Arthritis & rheumatology (Hoboken, N.J.) [print-electronic]. 2017 Jul; 69(7): 1418-28. PMID: 28334504, PMCID: PMC5489357, DOI: 10.1002/art.40104, ISSN: 2326-5205.

Plate L, Wiseman RL. Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy. Trends Cell Biol [print-electronic]. 2017 Jun 6/21/2017; PMID: 28647092, PII: S0962-8924(17)30085-5, DOI: 10.1016/j.tcb.2017.05.006, ISSN: 1879-3088.

Plate L, Cooley CB, Chen JJ, Paxman RJ, Gallagher CM, Madoux F, Genereux JC, Dobbs W, Garza D, Spicer TP, Scampavia L, Brown SJ, Rosen H, Powers ET, Walter P, Hodder P, Wiseman RL, Kelly JW. Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. Elife. 2016 Jul 7/20/2016; 5: PMID: 27435961, PMCID: PMC4954754, DOI: 10.7554/eLife.15550, ISSN: 2050-084X.

Plate L, Paxman RJ, Wiseman RL, Kelly JW. Modulating protein quality control. Elife. 2016 Jul 7/20/2016; 5: PMID: 27435959, PMCID: PMC4954752, DOI: 10.7554/eLife.18431, ISSN: 2050-084X.

Chen W, Dong J, Plate L, Mortenson DE, Brighty GJ, Li S, Liu Y, Galmozzi A, Lee PS, Hulce JJ, Cravatt BF, Saez E, Powers ET, Wilson IA, Sharpless KB, Kelly JW. Arylfluorosulfates Inactivate Intracellular Lipid Binding Protein(s) through Chemoselective SuFEx Reaction with a Binding Site Tyr Residue. J. Am. Chem. Soc [print-electronic]. 2016 Jun 6/15/2016; 138(23): 7353-64. PMID: 27191344, PMCID: PMC4909538, DOI: 10.1021/jacs.6b02960, ISSN: 1520-5126.

Cooley CB, Ryno LM, Plate L, Morgan GJ, Hulleman JD, Kelly JW, Wiseman RL. Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2014 Sep 9/9/2014; 111(36): 13046-51. PMID: 25157167, PMCID: PMC4246986, PII: 1406050111, DOI: 10.1073/pnas.1406050111, ISSN: 1091-6490.

Plate L, Marletta MA. Phosphorylation-dependent derepression by the response regulator HnoC in the Shewanella oneidensis nitric oxide signaling network. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2013 Nov 11/26/2013; 110(48): E4648-57. PMID: 24218564, PMCID: PMC3845109, PII: 1318128110, DOI: 10.1073/pnas.1318128110, ISSN: 1091-6490.

Plate L, Marletta MA. Nitric oxide-sensing H-NOX proteins govern bacterial communal behavior. Trends Biochem. Sci [print-electronic]. 2013 Nov; 38(11): 566-75. PMID: 24113192, PMCID: PMC3819143, PII: S0968-0004(13)00154-0, DOI: 10.1016/j.tibs.2013.08.008, ISSN: 0968-0004.

Ivanisevic J, Zhu ZJ, Plate L, Tautenhahn R, Chen S, O'Brien PJ, Johnson CH, Marletta MA, Patti GJ, Siuzdak G. Toward 'omic scale metabolite profiling: a dual separation-mass spectrometry approach for coverage of lipid and central carbon metabolism. Anal. Chem [print-electronic]. 2013 Jul 7/16/2013; 85(14): 6876-84. PMID: 23781873, PMCID: PMC3761963, DOI: 10.1021/ac401140h, ISSN: 1520-6882.

Plate L, Marletta MA. Nitric oxide modulates bacterial biofilm formation through a multicomponent cyclic-di-GMP signaling network. Mol. Cell [print-electronic]. 2012 May 5/25/2012; 46(4): 449-60. PMID: 22542454, PMCID: PMC3361614, PII: S1097-2765(12)00260-2, DOI: 10.1016/j.molcel.2012.03.023, ISSN: 1097-4164.

Carlson HK, Plate L, Price MS, Allen JJ, Shokat KM, Marletta MA. Use of a semisynthetic epitope to probe histidine kinase activity and regulation. Anal. Biochem [print-electronic]. 2010 Feb 2/15/2010; 397(2): 139-43. PMID: 19819215, PMCID: PMC2812668, PII: S0003-2697(09)00709-X, DOI: 10.1016/j.ab.2009.10.009, ISSN: 1096-0309.

Weinert EE, Plate L, Whited CA, Olea C, Marletta MA. Determinants of ligand affinity and heme reactivity in H-NOX domains. Angew. Chem. Int. Ed. Engl. 2010; 49(4): 720-3. PMID: 20017169, PMCID: PMC3517115, DOI: 10.1002/anie.200904799, ISSN: 1521-3773.

Hassan AQ, Wang Y, Plate L, Stubbe J. Methodology to probe subunit interactions in ribonucleotide reductases. Biochemistry. 2008 Dec 12/9/2008; 47(49): 13046-55. PMID: 19012414, PMCID: PMC2645937, DOI: 10.1021/bi8012559, ISSN: 1520-4995.

Gianolio DA, Philbrook M, Avila LZ, Young LE, Plate L, Santos MR, Bernasconi R, Liu H, Ahn S, Sun W, Jarrett PK, Miller RJ. Hyaluronan-tethered opioid depots: synthetic strategies and release kinetics in vitro and in vivo. Bioconjug. Chem [print-electronic]. 2008 Sep; 19(9): 1767-74. PMID: 18717537, DOI: 10.1021/bc8000479, ISSN: 1520-4812.