James Reid Gilmore PhD
Title | Professor Emeritus |
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Institution | University of Massachusetts Medical School |
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Department | Biochemistry and Molecular Pharmacology |
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Address | University of Massachusetts Medical School 364 Plantation Street, LRB Worcester MA 01605
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Phone | 508-856-5894 |
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vCard | Download vCard |
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Institution | UMMS - School of Medicine |
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Department | Biochemistry and Molecular Pharmacology |
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Institution | UMMS - Graduate School of Biomedical Sciences |
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Department | Biochemistry and Molecular Pharmacology |
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Institution | UMMS - Graduate School of Biomedical Sciences |
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Department | Interdisciplinary Graduate Program |
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Biography University of New Mexico Albuquerque, Albuquerque, NM, United States | BS | | Chemistry | University of Illinois, Urbana-Champaign, Champaign, IL, United States | MS | | Biochemistry | University of Illinois, Urbana-Champaign, Champaign, IL, United States | PHD | | Biochemistry |
Overview PhD, University of Illinois, Urbana, 1980 Postdoctoral Training The Rockefeller University, 1980-1983
Molecular mechanism of secretory protein translocation
The objective of research in our laboratory is to understand how proteins reach their final destinations within a cell. Specifically, we are investigating the biosynthesis, translocation, processing and folding of proteins in the rough endoplasmic reticulum. A major goal of our lab is to elucidate the mechanism of protein translocation across the rough endoplasmic reticulum (RER) membrane. The signal recognition particle (SRP), a ribonucleoprotein that binds to the polypeptide exit site on the ribosome, and the membrane bound SRP receptor (SR) function together to selectively attach a ribosome synthesizing a protein with an RER signal sequences to the Sec61 complex. The Sec61 heterotrimer forms an evolutionarily conserved channel for translocation of secreted proteins and integration of membrane proteins. We are using the Saccharomyces cerevisiae experimental to analyze the mechanism of translocation channel gating by ribosome-nascent chain complexes. Novel Sec61 mutants are designed based upon the structure of the Methanococcus janaschii SecYEb complex. The in vivo kinetics of protein translocation channel gating are being analyzed using ubiquitin translocation assay (UTA) reporters. Asparagine-linked glycosylation of proteins occurs within the lumen of the RER. Oligosaccharyltransferase (OST) catalyzes the transfer of a preassembled high-mannose oligosaccharide onto N-X-T or N-X-S acceptor sites (seqons) as the nascent polypeptide is transported into the RER lumen through the Sec61 complex. The oligosaccharide donor for the enzyme is the dolichol pyrophosphate linked oligosaccharide GlcNAc2Man9Glc3. The oligosaccharyltransferase is a hetero-octameric integral membrane protein in higher eukaryotes. Many unicellular protists have simpler OSTs with either a single subunit (e.g. Trypanosoma cruzi) or four subunits (e.g. Entamoeba histolytica). The active site subunit of the OST is the STT3 protein. Interestingly, the genomes of insects, plants and vertebrates encode two STT3 proteins. Biochemical experiments have revealed that the two SST3 proteins (STT3A and STT3B) assemble with a shared set of non-catalytic subunits into two separate OST complexes with different kinetic properties. We are analyzing the roles of these two distinct OST complexes in tissue culture cells by selectively knocking down STT3A or STT3B expression using siRNAs. Current evidence indicates that the STT3A isoform of the OST is primarily responsible for cotranslational glycosylation of nascent glycoproteins as the acceptor sequons exit the luminal face of the translocation channel. The STT3B isoform of the OST can modify skipped sequons on unfolded proteins in the lumen of the ER. Rotation Project BackgroundIn yeast cells, protein translocation across the endoplasmic reticulum can occur by cotranslational or posttranslational pathways. The objective of this project is to develop a rapid method to inactivate the posttranslational pathway in vivo in yeast cells by appending the CMV-ribosome stalling sequence to the C-terminus of a typical posttranslational translocation substrate (carboxypeptidase Y). Complexes between the posttranslational translocation channel (SEC complex) and the stalled ribosomes will be purified for structural and functional analysis. Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications.
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Cherepanova NA, Venev SV, Leszyk JD, Shaffer SA, Gilmore R. Quantitative glycoproteomics reveals new classes of STT3A- and STT3B-dependent N-glycosylation sites. J Cell Biol. 2019 Jul 11. PMID: 31296534.
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Klaver E, Zhao P, May M, Flanagan-Steet H, Freeze HH, Gilmore R, Wells L, Contessa J, Steet R. Selective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing. Dis Model Mech. 2019 Jun 05; 12(6). PMID: 31101650.
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Blommaert E, Péanne R, Cherepanova NA, Rymen D, Staels F, Jaeken J, Race V, Keldermans L, Souche E, Corveleyn A, Sparkes R, Bhattacharya K, Devalck C, Schrijvers R, Foulquier F, Gilmore R, Matthijs G. Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype. Proc Natl Acad Sci U S A. 2019 May 14; 116(20):9865-9870. PMID: 31036665.
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Lu H, Cherepanova NA, Gilmore R, Contessa JN, Lehrman MA. Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction. FASEB J. 2019 Jun; 33(6):6801-6812. PMID: 30811219.
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Chang IJ, Byers HM, Ng BG, Merritt JL, Gilmore R, Shrimal S, Wei W, Zhang Y, Blair AB, Freeze HH, Zhang B, Lam C. Factor VIII and vWF deficiency in STT3A-CDG. J Inherit Metab Dis. 2019 Mar; 42(2):325-332. PMID: 30701557.
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Shrimal S, Gilmore R. Oligosaccharyltransferase structures provide novel insight into the mechanism of asparagine-linked glycosylation in prokaryotic and eukaryotic cells. Glycobiology. 2018 Oct 11. PMID: 30312397.
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Lu H, Fermaintt CS, Cherepanova NA, Gilmore R, Yan N, Lehrman MA. Mammalian STT3A/B oligosaccharyltransferases segregate N-glycosylation at the translocon from lipid-linked oligosaccharide hydrolysis. Proc Natl Acad Sci U S A. 2018 09 18; 115(38):9557-9562. PMID: 30181269.
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Rinis N, Golden JE, Marceau CD, Carette JE, Van Zandt MC, Gilmore R, Contessa JN. Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors. Cell Chem Biol. 2018 10 18; 25(10):1231-1241.e4. PMID: 30078634.
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Mandon EC, Butova C, Lachapelle A, Gilmore R. Conserved motifs on the cytoplasmic face of the protein translocation channel are critical for the transition between resting and active conformations. J Biol Chem. 2018 Jul 09. PMID: 29986881.
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Braunger K, Pfeffer S, Shrimal S, Gilmore R, Berninghausen O, Mandon EC, Becker T, Förster F, Beckmann R. Structural basis for coupling protein transport and N-glycosylation at the mammalian endoplasmic reticulum. Science. 2018 04 13; 360(6385):215-219. PMID: 29519914.
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Wei W, Misra S, Cannon MV, Yang R, Zhu X, Gilmore R, Zhu M, Zhang B. Molecular mechanisms of missense mutations that generate ectopic N-glycosylation sites in coagulation factor VIII. Biochem J. 2018 Mar 06; 475(5):873-886. PMID: 29444815.
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Shrimal S, Cherepanova NA, Gilmore R. One flexible loop in OST lassos both substrates. Nat Struct Mol Biol. 2017 Dec 07; 24(12):1009-1010. PMID: 29215637.
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Shrimal S, Cherepanova NA, Gilmore R. DC2 and KCP2 mediate the interaction between the oligosaccharyltransferase and the ER translocon. J Cell Biol. 2017 Aug 31. PMID: 28860277.
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Lin DL, Cherepanova NA, Bozzacco L, MacDonald MR, Gilmore R, Tai AW. Dengue Virus Hijacks a Noncanonical Oxidoreductase Function of a Cellular Oligosaccharyltransferase Complex. MBio. 2017 Jul 18; 8(4). PMID: 28720733.
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Tripathi A, Mandon EC, Gilmore R, Rapoport TA. Two alternative binding mechanisms connect the protein translocation Sec71/Sec72 complex with heat shock proteins. J Biol Chem. 2017 Mar 12. PMID: 28286332.
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Lopez-Sambrooks C, Shrimal S, Khodier C, Flaherty DP, Rinis N, Charest JC, Gao N, Zhao P, Wells L, Lewis TA, Lehrman MA, Gilmore R, Golden JE, Contessa JN. Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells. Nat Chem Biol. 2016 Dec; 12(12):1023-1030. PMID: 27694802.
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Cherepanova N, Shrimal S, Gilmore R. N-linked glycosylation and homeostasis of the endoplasmic reticulum. Curr Opin Cell Biol. 2016 Aug; 41:57-65. PMID: 27085638.
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Cherepanova NA, Gilmore R. Mammalian cells lacking either the cotranslational or posttranslocational oligosaccharyltransferase complex display substrate-dependent defects in asparagine linked glycosylation. Sci Rep. 2016 Feb 11; 6:20946. PMID: 26864433.
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Shrimal S, Gilmore R. Reduced expression of the oligosaccharyltransferase exacerbates protein hypoglycosylation in cells lacking the fully assembled oligosaccharide donor. Glycobiology. 2015 Jul; 25(7):774-83. PMID: 25792706.
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Shrimal S, Cherepanova NA, Gilmore R. Cotranslational and posttranslocational N-glycosylation of proteins in the endoplasmic reticulum. Semin Cell Dev Biol. 2015 May; 41:71-8. PMID: 25460543.
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Cherepanova NA, Shrimal S, Gilmore R. Oxidoreductase activity is necessary for N-glycosylation of cysteine-proximal acceptor sites in glycoproteins. J Cell Biol. 2014 Aug 18; 206(4):525-39. PMID: 25135935.
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Shrimal S, Gilmore R. Glycosylation of closely spaced acceptor sites in human glycoproteins. J Cell Sci. 2013 Dec 1; 126(Pt 23):5513-23. PMID: 24105266.
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Shrimal S, Ng BG, Losfeld ME, Gilmore R, Freeze HH. Mutations in STT3A and STT3B cause two congenital disorders of glycosylation. Hum Mol Genet. 2013 Nov 15; 22(22):4638-45. PMID: 23842455.
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Shrimal S, Trueman SF, Gilmore R. Extreme C-terminal sites are posttranslocationally glycosylated by the STT3B isoform of the OST. J Cell Biol. 2013 Apr 1; 201(1):81-95. PMID: 23530066.
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Mandon EC, Trueman SF, Gilmore R. Protein translocation across the rough endoplasmic reticulum. Cold Spring Harb Perspect Biol. 2013 Feb 01; 5(2). PMID: 23251026.
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Trueman SF, Mandon EC, Gilmore R. A gating motif in the translocation channel sets the hydrophobicity threshold for signal sequence function. J Cell Biol. 2012 Dec 10; 199(6):907-18. PMID: 23229898.
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Gilmore R, Mandon EC. Understanding integration of a-helical membrane proteins: the next steps. Trends Biochem Sci. 2012 Aug; 37(8):303-8. PMID: 22748693.
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Zhang X, Garbett K, Veeraraghavalu K, Wilburn B, Gilmore R, Mirnics K, Sisodia SS. A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. J Neurosci. 2012 Jun 20; 32(25):8633-48. PMID: 22723704.
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Trueman SF, Mandon EC, Gilmore R. Translocation channel gating kinetics balances protein translocation efficiency with signal sequence recognition fidelity. Mol Biol Cell. 2011 Sep; 22(17):2983-93. PMID: 21737680.
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Gilmore R. Structural biology: Porthole to catalysis. Nature. 2011 Jun 15; 474(7351):292-3. PMID: 21677742.
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Bas T, Gao GY, Lvov A, Chandrasekhar KD, Gilmore R, Kobertz WR. Post-translational N-glycosylation of type I transmembrane KCNE1 peptides: implications for membrane protein biogenesis and disease. J Biol Chem. 2011 Aug 12; 286(32):28150-9. PMID: 21676880.
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Becker T, Bhushan S, Jarasch A, Armache JP, Funes S, Jossinet F, Gumbart J, Mielke T, Berninghausen O, Schulten K, Westhof E, Gilmore R, Mandon EC, Beckmann R. Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome. Science. 2009 Dec 4; 326(5958):1369-73. PMID: 19933108.
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Mandon EC, Trueman SF, Gilmore R. Translocation of proteins through the Sec61 and SecYEG channels. Curr Opin Cell Biol. 2009 Aug; 21(4):501-7. PMID: 19450960.
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Ruiz-Canada C, Kelleher DJ, Gilmore R. Cotranslational and posttranslational N-glycosylation of polypeptides by distinct mammalian OST isoforms. Cell. 2009 Jan 23; 136(2):272-83. PMID: 19167329.
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Magnelli P, Cipollo JF, Ratner DM, Cui J, Kelleher D, Gilmore R, Costello CE, Robbins PW, Samuelson J. Unique Asn-linked oligosaccharides of the human pathogen Entamoeba histolytica. J Biol Chem. 2008 Jun 27; 283(26):18355-64. PMID: 18417475.
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Jiang Y, Cheng Z, Mandon EC, Gilmore R. An interaction between the SRP receptor and the translocon is critical during cotranslational protein translocation. J Cell Biol. 2008 Mar 24; 180(6):1149-61. PMID: 18347066.
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Banerjee S, Vishwanath P, Cui J, Kelleher DJ, Gilmore R, Robbins PW, Samuelson J. The evolution of N-glycan-dependent endoplasmic reticulum quality control factors for glycoprotein folding and degradation. Proc Natl Acad Sci U S A. 2007 Jul 10; 104(28):11676-81. PMID: 17606910.
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Kelleher DJ, Banerjee S, Cura AJ, Samuelson J, Gilmore R. Dolichol-linked oligosaccharide selection by the oligosaccharyltransferase in protist and fungal organisms. J Cell Biol. 2007 Apr 9; 177(1):29-37. PMID: 17403929.
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Mandon EC, Gilmore R. The tail end of membrane insertion. Cell. 2007 Mar 23; 128(6):1031-2. PMID: 17382875.
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Cheng Z, Gilmore R. Slow translocon gating causes cytosolic exposure of transmembrane and lumenal domains during membrane protein integration. Nat Struct Mol Biol. 2006 Oct; 13(10):930-6. PMID: 16980973.
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Kelleher DJ, Gilmore R. An evolving view of the eukaryotic oligosaccharyltransferase. Glycobiology. 2006 Apr; 16(4):47R-62R. PMID: 16317064.
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Karamyshev AL, Kelleher DJ, Gilmore R, Johnson AE, von Heijne G, Nilsson I. Mapping the interaction of the STT3 subunit of the oligosaccharyl transferase complex with nascent polypeptide chains. J Biol Chem. 2005 Dec 9; 280(49):40489-93. PMID: 16216884.
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Samuelson J, Banerjee S, Magnelli P, Cui J, Kelleher DJ, Gilmore R, Robbins PW. The diversity of dolichol-linked precursors to Asn-linked glycans likely results from secondary loss of sets of glycosyltransferases. Proc Natl Acad Sci U S A. 2005 Feb 1; 102(5):1548-53. PMID: 15665075.
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Cheng Z, Jiang Y, Mandon EC, Gilmore R. Identification of cytoplasmic residues of Sec61p involved in ribosome binding and cotranslational translocation. J Cell Biol. 2005 Jan 3; 168(1):67-77. PMID: 15631991.
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Mandon EC, Gilmore R. GTPase twins in the SRP family. Nat Struct Mol Biol. 2004 Feb; 11(2):115-6. PMID: 14749771.
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Mandon EC, Jiang Y, Gilmore R. Dual recognition of the ribosome and the signal recognition particle by the SRP receptor during protein targeting to the endoplasmic reticulum. J Cell Biol. 2003 Aug 18; 162(4):575-85. PMID: 12913112.
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Wu X, Rush JS, Karaoglu D, Krasnewich D, Lubinsky MS, Waechter CJ, Gilmore R, Freeze HH. Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij. Hum Mutat. 2003 Aug; 22(2):144-50. PMID: 12872255.
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Kelleher DJ, Karaoglu D, Mandon EC, Gilmore R. Oligosaccharyltransferase isoforms that contain different catalytic STT3 subunits have distinct enzymatic properties. Mol Cell. 2003 Jul; 12(1):101-11. PMID: 12887896.
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Nilsson I, Kelleher DJ, Miao Y, Shao Y, Kreibich G, Gilmore R, von Heijne G, Johnson AE. Photocross-linking of nascent chains to the STT3 subunit of the oligosaccharyltransferase complex. J Cell Biol. 2003 May 26; 161(4):715-25. PMID: 12756234.
This graph shows the total number of publications by year, by first, middle/unknown, or last author.
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Year | Publications |
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2003 | 4 | 2004 | 1 | 2005 | 4 | 2006 | 1 | 2007 | 3 | 2008 | 2 | 2009 | 3 | 2011 | 3 | 2012 | 3 | 2013 | 4 | 2014 | 2 | 2015 | 1 | 2016 | 3 | 2017 | 4 | 2018 | 6 | 2019 | 5 |
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