PNNL

John is an accomplished lipid biochemist and structural biologist with an interest in understanding molecular pathology of disease. He earned his Ph.D. from Wake Forest School of Medicine where he received training in lipid biochemistry under the late Dr. Lawrence Rudel studying the role of low-density lipoproteins (LDL) in the initiation of cardiovascular disease. He rounded out his training during his postdoctoral fellowship under Dr. Sean Davidson at the University of Cincinnati developing sophisticated lipoprotein separation technologies and mass spectrometry applications to define the compositional and structural details of high-density lipoproteins. His work has resulted in numerous publications, invited speakerships and accolades including a Spotlight Award from Journal of Lipid Research recognizing him as a “Rising Star in the Lipid Field.” In addition to his lipoprotein research, John is involved in the development of high-throughput structural proteomics technologies leveraging mass spectrometry to define the key structural changes in proteins that allow them to bind complementary partners and drive molecular function.

John currently serves as a Senior Scientist and Chemical Biology Team Lead in the Biological Sciences Division. He is an active member of the American Heart Association's Council on Arteriosclerosis, Thrombosis, and Vascular Biology and holds joint appointments in the Department of Pathology and Laboratory Medicine at the University of Cincinnati and Department of Neurology at Oregon Health Sciences University. He continues his theme of developing and applying cutting-edge technologies to probe difficult-to-study macromolecular complexes such as lipoproteins which is supported by funding from multiple agencies including the Department of Energy and National Institutes of Health. John also happily serves as a mentor to junior scientists to foster their growth and development within PNNL and their field of interest.

John participates in a broad range of studies but has a specific focus on the interplay between lipoprotein metabolism and human disease. Lipoproteins are nanosized complexes lipids and proteins responsible for extracellular lipid transport in the body. Recent research has shown that lipoproteins are a constellation of compositionally distinct and diverse subspecies that, in addition to lipid transport, modulate the immune (host) response, oxidative stress, glucose metabolism, platelet function, and inflammation. Unique lipoprotein populations are generated from the liver, intestine, lung and brain and changes in these populations are associated with cardiovascular disease, heart failure, atheroma plaque rupture, sepsis, type-2 diabetes, obesity, pregnancy, and neurological disorders such as Alzheimer’s disease. Our goals are to:

1. Molecularly profile lipoprotein subspecies from biofluids such as plasma, cerebrospinal fluid, and bronchoalveolar lavage fluid
2. Determine the structural organization of apolipoprotein scaffolds on the lipid surface and how these conformations shift in response to lipid packaging
3. Reveal how these conformational adaptations modulate particle interaction with modifying cofactors and cell-surface receptors to drive biological function.
4. Profile the cellular response to lipoprotein docking and cargo delivery

To achieve these objectives, our team develops and applies a variety of cutting-edge technologies:

• Ultra-sensitive fluorescent lipoprotein profiler to speciate particles
• Generation of synthetic lipid nanodiscs for structural studies of scaffolds and membrane proteins
• Proteomics and lipidomics for molecular profiling
• Structural proteomics (cryo-electron microscopy, chemical cross-linking, limited proteolysis, thermal proteome profiling)

• Ph.D. in Molecular Pathology, Wake Forest School of Medicine
• B.S.E. in Mechanical Engineering, University of Michigan

• Affiliate Assistant Professor, Department of Neurology, Oregon Health Sciences University, Portland, OR
• Visiting Scholar, Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH

• Spotlight Award: “Rising star in Lipid Field” by the Journal of Lipid Research, 2019

1. Merrill NJ, Davidson WS, He Y, Ludovico ID, Sarkar S, Berger MR, McDermott JE, Van Eldik LJ, Wilcock DM, Monroe ME, Kyle JE, Bruce KD, Heinecke JW, Vaisar T, Raber J, Quinn JF, Melchior JT. Human cerebrospinal fluid contains diverse lipoprotein subspecies enriched in proteins implicated in central nervous system health.  Science Advances. 2023 Sep;9(35). PMID: 37647397
2. Woo JG, Melchior JT, Swertfeger DK, Remaley AT, Sise EA, Sosseh F, Welge JA, Prentice AM, Davidson WS, Moore SE, Woollett LA. Lipoprotein subfraction patterns throughout gestation in The Gambia: changes in subfraction composition and their relationships with infant birth weights.  Lipids Health Dis. 2023 Feb 3;22(1):19. PMID: 36737730.
3. Sarkar S, Melchior JT, Henry HR, Syed F, Mirmira RG, Nakayasu ES, Metz TO. GDF15: a potential therapeutic target for type 1 diabetes.  Expert Opin Ther Targets 2022 Jan;26(1):57-67. PMID: 35138971.
4. Melchior JT, Swertfeger DK, Morris J, Street SE, Warshak CR, Welge JA, Remaley AT, Catov JM, Davidson WS, Woollett LA. Pregnancy is accompanied by larger high-density lipoprotein particles and compositionally distinct subspecies.  J. Lipid Res.  2021 Aug;62:100107. PMID: 34416270.
5. Melchior JT, Street SE, Vaisar T, Hart R, Jerome J, Kuklenyik Z, Clouet-Foraison N, Thronock C, Bedi S, Shah AS, Segrest JP, Heinecke JW, Davidson WS. Apolipoprotein A-I modulates HDL particle size in the absence of apolipoprotein A-II.  J. Lipid Res.  2021 Jul;62:100099 PMID: 34324889.
6. May-Zhang LS, Yermalitsky V, Melchior JT, Morris J, Tallman KA, Borja MS, Pleasant T, Amarnath V, Song W, Yancey PG, Davidson WS, MacRae LF, Davies SS. Modified sites and functional consequences of 4-oxo2-nonenal adducts in HDL that are elevated in familial hypercholesterolemia. J Biol. Chem. 2019. 294(50):19022-33. PMID: 31666337.
7. Furtado JD, Yamamoto R, Melchior JT, Andraski AB, Gamez-Guerrero M, Mulcahy P, He Z, Cai T, Davidson WS, Sacks FM. Distinct proteomic signatures in 16 HDL subspecies. Arterioscler. Thromb. and Vasc. Biol. 2018. 38(12):2827-2842. PMID: 30571168.
8. Cooke AL, Morris J, Melchior JT, Street SE, Jerome WG, Huang R, Herr AB, Smith LE, Segrest JP, Remaley AT, Shah AS, Thompson TB, Davidson WS. A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL. J. Lipid Res.  2018 Jul;59(7):1244-1255. PMID: 29773713.
9. Li, H, Shah, AS, Zhu X, Swertfeger D, Ren Sheng, Melchior JT, Gordon S, Davidson WS, Lu JL. High density lipoproteins-associated proteins and subspecies related to arterial stiffness in young adults with type 2 diabetes mellitus.  Complexity. 2018.
10. Melchior JT*, Lima DB, Barbosa VC, Chamot-Rooke J, Gozzo FC, Brasil T, Fisher JS, Carvalho PC, Davidson WS. Characterizing homodimers by isotopically labeled proteins analyzed with cross-linking and mass spectrometry. Nat. Protocols. 2018. 13(3):431-458. *Co-first Author. PMID: 29388937.
11. Rebholz SL, Melchior JT, Welge JA, Remaley AT, Davidson WS, Woollett LA.  Effects of Multiple Freeze/Thaw Cycles on Measurements of Potential Novel Biomarkers Associated with Adverse Pregnancy Outcomes. J. Clin. Lab. Med. 2017. 2(1). PMID: 29226278.
12. Melchior JT, Walker RG, Cooke AL, Morris J, Jones MK, Sorci-Thomas MG, Thomas MJ, Heinecke JW, Atkinson D, Rye KA, Barter PJ, Lund-Katz S, Phillips MC, Segrest JP, Thompson TB, Davidson WS. A Consensus Model of Human Apolipoprotein A-I in its Monomeric and Lipid-free State.  Nat Struct Mol Biol. 2017. 24(12):1093-1099. PMID: 29131142.
13. Rebholz SL, Melchior JT, Davidson WS, Jones HN, Welge JA, Prentice AM, Moore SE, Woollett LA. Studies in genetically modified mice implicate maternal HDL as a mediator of fetal growth. FASEB J. 2018. 32(2):717727. PMID: 28982731.
14. Davidson WS, Heink A, Sexsmith H, Dolan LM, Gordon SM, Otvos JD, Melchior JT, Elder DA, Khoury J, Geh E, Shah AS. Obesity is associated with an altered HDL subspecies profile among adolescents with metabolic disease. J. Lipid Res.  2017 Sep;58(9):1916-1923. PMID: 28743729.
15. Rueda CM, Rodgriguez-Perea AL, Moreno-Fernandez M, Jackson CM, Melchior JT, Davidson WS, Cougnet CA. High density lipoproteins selectively promote the survival of human regulatory T-cells. J. Lipid Res.  2017. 58(8):1514-1523. PMID: 28377425.
16. Melchior JT, Street SE, Andraski AB, Furtado JD, Sacks FM, Shute RL, Greve EI, Swertfeger DK, Li H, Shah AS, Lu JL, Davidson WS.  Apolipoprotein A-II alters the proteome of human high-density lipoproteins and enhances cholesterol efflux from ABCA1. J. Lipid Res.  2017. 58(7):1374-1385. PMID: 28476857.
17. Davidson WS, Inge TH, Sexmith H, Heink A, Elder D, Hui DY, Melchior JT, Kelesidis T, Shah AS. Weight loss surgery in adolescents corrects high-density subspecies and their function.  Int. J. Obes.  2017. 41(1):8389. PMID: 27780977.
18. Davidson WS, Heink A, Sexmith H, Melchior JT, Gordon SM, Kuklenyik Z, Woollett L, Barr JR, Jones JI, Toth CA, Shah AS.  The effects of apolipoprotein B depletion on HDL subspecies composition and function.  J. Lipid Res.  2016. 57(4):674-86. PMID: 26908829.
19. Melchior JT, Walker RG, Morris J, Jones MK, Segrest JP, Lima DB, Carvalho PC, Gozzo FC, Castleberry M, Thompson TB, Davidson WS.  An Evaluation of the Crystal Structure of C-terminal Truncated Apolipoprotein A-I in Solution Reveals Structural Dynamics Related to Lipid Binding.  J Biol. Chem. 2016. 291(10):439-51. PMID: 26755744.
20. Melchior JT, Olson JD, Kelley KL, Wilson MD, Sawyer JK, Link KM, Rudel LL.  Targeted Knockdown of Hepatic SOAT2 With Antisense Oligonucleotides Stabilizes Atherosclerotic Plaque in ApoB100-only LDLr-/- Mice.  Arterioscler. Thromb. and Vasc. Biol. 2015. 35(9):1920-7. PMID: 26229140.
21. Walker RG, Deng X, Melchior JT, Morris J, Tso P, Jones MK, Segrest JP, Thompson TB, Davidson WS. The Structure of Human Apolipoprotein A-IV as Revealed by Stable Isotope Assisted Cross-linking, Molecular Dynamics and Small Angle X-ray Scattering.  J Biol. Chem. 2014. 289(9):5596-608. PMID: 24425874.
22. Thomas G, Betters JL, Lord CC, Brown AL, Marshall S, Ferguson D, Sawyer J, Davis MA, Melchior JT, Blume LC, Howlett AC, Ivanova PT, Milne SB, Myers DS, Mrak I, Leber V, Heier C, Taschler U, Blankman JL, Cravatt BF, Lee RG, Crooke RM, Graham MJ, Zimmermann R, Brown HA, Brown JM.  The Serine Hydrolase ABHD6 is a Critical Regulator of the Metabolic Syndrome. Cell Rep. 2013. 31;5(2):508-20. PMID: 24095738.
23. Melchior JT, Sawyer JK, Kelley KL, Shah R, Wilson MD, Hantgan RR, Rudel LL.  LDL Particle Core Enrichment in Cholesteryl Oleate Increases Proteoglycan Binding and Promotes Atherosclerosis.  J. Lipid Res.  2013 Sep; 54(9):2495-503. PMID: 23804810.
24. Brown JM, Betters JL, Lord C, Ma Y, Han X, Yank K, Alger HM, Melchior J, Sawyer J, Shah R, Wilson MD, Liu X, Graham MJ, Lee R, Crooke R, Shulman GI, Xue B, Shi H, Yu L.  CGI-58 Knockdown in Mice Causes Hepatic Steatosis but Prevents Diet-Induced Obesity and Glucose Intolerance.  J. Lipid Res.  2010 Nov; 51(11):3306-15. PMID: 20802159.