Welcome

Research Interests

Integrative Biology Graduate Program
Molecular Biophysics Graduate Program

Studies in our laboratory focus on the folding, structure, and function of integral membrane proteins and their misfolding as the basis of human disease. The cystic fibrosis conductance regulator (CFTR) and microbial homologues have served as our favored models for the bulk of these biophysical, molecular biological, and cell biological studies. These proteins are members of the ABC transporter supergene family of ATP-dependent active transporters and channels. This supergene family is the largest in many of the completely sequenced microbial genomes and includes many medically relevant members, including ATP-driven drug efflux pumps and bacterial toxin transporters, in addition to CFTR. Mutations in CTFR (>900 to date) cause the fatal recessive disorder cystic fibrosis (CF). Many of these mutations alter the ability of the membrane protein to efficiently fold into a functional structure. Others alter the mechano-chemistry of the transport gating cycle. Understanding these defects at a molecular level is providing insight into how primary sequence encodes the folding pattern of integral membrane proteins, how cellular systems cope with the aberrant protein, and how the energy of ATP hydrolysis is utilized to effect movement of a solute across a membrane barrier.

Publications

Isogenic cell models of cystic fibrosis-causing variants in natively expressing pulmonary epithelial cells.
Valley HC, Bukis KM, Bell A, Cheng Y, Wong E, Jordan NJ, Allaire NE, Sivachenko A, Liang F, Bihler H, Thomas PJ, Mahiou J, Mense M.
J Cyst Fibros. 2019 Jul;18(4):476-483. doi: 10.1016/j.jcf.2018.12.001. Epub 2018 Dec 15.
PMID: 30563749

CFTR modulator theratyping: Current status, gaps and future directions.
Clancy JP, Cotton CU, Donaldson SH, Solomon GM, VanDevanter DR, Boyle MP, Gentzsch M, Nick JA, Illek B, Wallenburg JC, Sorscher EJ, Amaral MD, Beekman JM, Naren AP, Bridges RJ, Thomas PJ, Cutting G, Rowe S, Durmowicz AG, Mense M, Boeck KD, Skach W, Penland C, Joseloff E, Bihler H, Mahoney J, Borowitz D, Tuggle KL.
J Cyst Fibros. 2019 Jan;18(1):22-34. doi: 10.1016/j.jcf.2018.05.004. Epub 2018 Jun 20.
PMID: 29934203 Free PMC article. Review.

Pathogenic Signal Sequence Mutations in Progranulin Disrupt SRP Interactions Required for mRNA Stability.
Pinarbasi ES, Karamyshev AL, Tikhonova EB, Wu IH, Hudson H, Thomas PJ.
Cell Rep. 2018 Jun 5;23(10):2844-2851. doi: 10.1016/j.celrep.2018.05.003.
PMID: 29874572 Free PMC article.

Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization.
Pinarbasi ES, Ca─čatay T, Fung HYJ, Li YC, Chook YM, Thomas PJ.
Sci Rep. 2018 May 4;8(1):7083. doi: 10.1038/s41598-018-25008-4.
PMID: 29728608 Free PMC article.

17β-Estradiol Dysregulates Innate Immune Responses to Pseudomonas aeruginosa Respiratory Infection and Is Modulated by Estrogen Receptor Antagonism.
Abid S, Xie S, Bose M, Shaul PW, Terada LS, Brody SL, Thomas PJ, Katzenellenbogen JA, Kim SH, Greenberg DE, Jain R.
Infect Immun. 2017 Sep 20;85(10):e00422-17. doi: 10.1128/IAI.00422-17. Print 2017 Oct.
PMID: 28784925 Free PMC article.

Direct Binding of the Corrector VX-809 to Human CFTR NBD1: Evidence of an Allosteric Coupling between the Binding Site and the NBD1:CL4 Interface.
Hudson RP, Dawson JE, Chong PA, Yang Z, Millen L, Thomas PJ, Brouillette CG, Forman-Kay JD.
Mol Pharmacol. 2017 Aug;92(2):124-135. doi: 10.1124/mol.117.108373. Epub 2017 May 25.
PMID: 28546419

Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding.
Huerta C, Jiang X, Trevino I, Bender CF, Ferguson DA, Probst B, Swinger KK, Stoll VS, Thomas PJ, Dulubova I, Visnick M, Wigley WC.
Biochim Biophys Acta. 2016 Nov;1860(11 Pt A):2537-2552. doi: 10.1016/j.bbagen.2016.07.026. Epub 2016 Jul 27.
PMID: 27474998

N-Alpha-Acetyltransferases and Regulation of CFTR Expression.
Vetter AJ, Karamyshev AL, Patrick AE, Hudson H, Thomas PJ.
PLoS One. 2016 May 16;11(5):e0155430. doi: 10.1371/journal.pone.0155430. eCollection 2016.
PMID: 27182737 Free PMC article.

The BiP molecular chaperone plays multiple roles during the biogenesis of torsinA, an AAA+ ATPase associated with the neurological disease early-onset torsion dystonia.
Zacchi LF, Wu HC, Bell SL, Millen L, Paton AW, Paton JC, Thomas PJ, Zolkiewski M, Brodsky JL.
J Biol Chem. 2014 May 2;289(18):12727-47. doi: 10.1074/jbc.M113.529123. Epub 2014 Mar 13.
PMID: 24627482 Free PMC article.

Inefficient SRP interaction with a nascent chain triggers a mRNA quality control pathway.
Karamyshev AL, Patrick AE, Karamysheva ZN, Griesemer DS, Hudson H, Tjon-Kon-Sang S, Nilsson I, Otto H, Liu Q, Rospert S, von Heijne G, Johnson AE, Thomas PJ.
Cell. 2014 Jan 16;156(1-2):146-57. doi: 10.1016/j.cell.2013.12.017.
PMID: 24439374 Free PMC article.

Regulatory R region of the CFTR chloride channel is a dynamic integrator of phospho-dependent intra- and intermolecular interactions.
Bozoky Z, Krzeminski M, Muhandiram R, Birtley JR, Al-Zahrani A, Thomas PJ, Frizzell RA, Ford RC, Forman-Kay JD.
Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4427-36. doi: 10.1073/pnas.1315104110. Epub 2013 Nov 4.
PMID: 24191035 Free PMC article.

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.
Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR.
Nat Genet. 2013 Oct;45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.
PMID: 23974870 Free PMC article.

Development of CFTR Structure.
Patrick AE, Thomas PJ.
Front Pharmacol. 2012 Sep 6;3:162. doi: 10.3389/fphar.2012.00162. eCollection 2012.
PMID: 22973227 Free PMC article.

TDP-43 identified from a genome wide RNAi screen for SOD1 regulators.
Somalinga BR, Day CE, Wei S, Roth MG, Thomas PJ.
PLoS One. 2012;7(4):e35818. doi: 10.1371/journal.pone.0035818. Epub 2012 Apr 26.
PMID: 22563406 Free PMC article.

Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.
Mendoza JL, Schmidt A, Li Q, Nuvaga E, Barrett T, Bridges RJ, Feranchak AP, Brautigam CA, Thomas PJ.
Cell. 2012 Jan 20;148(1-2):164-74. doi: 10.1016/j.cell.2011.11.023.
PMID: 22265409 Free PMC article.

Alteration of CFTR transmembrane span integration by disease-causing mutations.
Patrick AE, Karamyshev AL, Millen L, Thomas PJ.
Mol Biol Cell. 2011 Dec;22(23):4461-71. doi: 10.1091/mbc.E11-05-0396. Epub 2011 Oct 12.
PMID: 21998193 Free PMC article.

A screen to identify cellular modulators of soluble levels of an amyotrophic lateral sclerosis (ALS)-causing mutant SOD1.
Somalinga BR, Miller GA, Malik HT, Wigley WC, Thomas PJ.
J Biomol Screen. 2011 Oct;16(9):974-85. doi: 10.1177/1087057111418505. Epub 2011 Aug 29.
PMID: 21875953 Free PMC article.

Biochemical and biophysical approaches to probe CFTR structure.
Schmidt A, Mendoza JL, Thomas PJ.
Methods Mol Biol. 2011;741:365-76. doi: 10.1007/978-1-61779-117-8_24.
PMID: 21594797 Free PMC article.

Introduction to section IV: biophysical methods to approach CFTR structure.
Mendoza JL, Schmidt A, Thomas PJ.
Methods Mol Biol. 2011;741:321-7. doi: 10.1007/978-1-61779-117-8_21.
PMID: 21594794 Free PMC article.

CFTR Folding Consortium: methods available for studies of CFTR folding and correction.
Peters KW, Okiyoneda T, Balch WE, Braakman I, Brodsky JL, Guggino WB, Penland CM, Pollard HB, Sorscher EJ, Skach WR, Thomas PJ, Lukacs GL, Frizzell RA.
Methods Mol Biol. 2011;742:335-53. doi: 10.1007/978-1-61779-120-8_20.
PMID: 21547742 Free PMC article.

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway.
Yang D, Li Q, So I, Huang CL, Ando H, Mizutani A, Seki G, Mikoshiba K, Thomas PJ, Muallem S.
J Clin Invest. 2011 Mar;121(3):956-65. doi: 10.1172/JCI43475. Epub 2011 Feb 7.
PMID: 21317537 Free PMC article.

The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain.
Hoelen H, Kleizen B, Schmidt A, Richardson J, Charitou P, Thomas PJ, Braakman I.
PLoS One. 2010 Nov 30;5(11):e15458. doi: 10.1371/journal.pone.0015458.
PMID: 21152102 Free PMC article.

Abnormal neurites containing C-terminally truncated alpha-synuclein are present in Alzheimer's disease without conventional Lewy body pathology.
Lewis KA, Su Y, Jou O, Ritchie C, Foong C, Hynan LS, White CL 3rd, Thomas PJ, Hatanpaa KJ.
Am J Pathol. 2010 Dec;177(6):3037-50. doi: 10.2353/ajpath.2010.100552. Epub 2010 Nov 5.
PMID: 21056999 Free PMC article.

Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening.
Kalid O, Mense M, Fischman S, Shitrit A, Bihler H, Ben-Zeev E, Schutz N, Pedemonte N, Thomas PJ, Bridges RJ, Wetmore DR, Marantz Y, Senderowitz H.
J Comput Aided Mol Des. 2010 Dec;24(12):971-91. doi: 10.1007/s10822-010-9390-0. Epub 2010 Oct 26.
PMID: 20976528 Free PMC article.

A unique redox-sensing sensor II motif in TorsinA plays a critical role in nucleotide and partner binding.
Zhu L, Millen L, Mendoza JL, Thomas PJ.
J Biol Chem. 2010 Nov 26;285(48):37271-80. doi: 10.1074/jbc.M110.123471. Epub 2010 Sep 22.
PMID: 20861018 Free PMC article.

The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis.
Thibodeau PH, Richardson JM 3rd, Wang W, Millen L, Watson J, Mendoza JL, Du K, Fischman S, Senderowitz H, Lukacs GL, Kirk K, Thomas PJ.
J Biol Chem. 2010 Nov 12;285(46):35825-35. doi: 10.1074/jbc.M110.131623. Epub 2010 Jul 28.
PMID: 20667826 Free PMC article.

Accelerated formation of alpha-synuclein oligomers by concerted action of the 20S proteasome and familial Parkinson mutations.
Lewis KA, Yaeger A, DeMartino GN, Thomas PJ.
J Bioenerg Biomembr. 2010 Feb;42(1):85-95. doi: 10.1007/s10863-009-9258-y. Epub 2010 Feb 11.
PMID: 20148295 Free PMC article.

Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis.
Hutt DM, Herman D, Rodrigues AP, Noel S, Pilewski JM, Matteson J, Hoch B, Kellner W, Kelly JW, Schmidt A, Thomas PJ, Matsumura Y, Skach WR, Gentzsch M, Riordan JR, Sorscher EJ, Okiyoneda T, Yates JR 3rd, Lukacs GL, Frizzell RA, Manning G, Gottesfeld JM, Balch WE.
Nat Chem Biol. 2010 Jan;6(1):25-33. doi: 10.1038/nchembio.275. Epub 2009 Dec 6.
PMID: 19966789 Free PMC article.

NMR evidence for differential phosphorylation-dependent interactions in WT and DeltaF508 CFTR.
Kanelis V, Hudson RP, Thibodeau PH, Thomas PJ, Forman-Kay JD.
EMBO J. 2010 Jan 6;29(1):263-77. doi: 10.1038/emboj.2009.329. Epub 2009 Nov 19.
PMID: 19927121 Free PMC article.

The torsin-family AAA+ protein OOC-5 contains a critical disulfide adjacent to Sensor-II that couples redox state to nucleotide binding.
Zhu L, Wrabl JO, Hayashi AP, Rose LS, Thomas PJ.
Mol Biol Cell. 2008 Aug;19(8):3599-612. doi: 10.1091/mbc.e08-01-0015. Epub 2008 Jun 11.
PMID: 18550799 Free PMC article.

Congenital chloride-losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3.
Dorwart MR, Shcheynikov N, Baker JM, Forman-Kay JD, Muallem S, Thomas PJ.
J Biol Chem. 2008 Mar 28;283(13):8711-22. doi: 10.1074/jbc.M704328200. Epub 2008 Jan 23.
PMID: 18216024 Free PMC article.

Solubilizing mutations used to crystallize one CFTR domain attenuate the trafficking and channel defects caused by the major cystic fibrosis mutation.
Pissarra LS, Farinha CM, Xu Z, Schmidt A, Thibodeau PH, Cai Z, Thomas PJ, Sheppard DN, Amaral MD.
Chem Biol. 2008 Jan;15(1):62-9. doi: 10.1016/j.chembiol.2007.11.012.
PMID: 18215773

Building an understanding of cystic fibrosis on the foundation of ABC transporter structures.
Mendoza JL, Thomas PJ.
J Bioenerg Biomembr. 2007 Dec;39(5-6):499-505. doi: 10.1007/s10863-007-9117-7.
PMID: 18080175

CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices.
Baker JM, Hudson RP, Kanelis V, Choy WY, Thibodeau PH, Thomas PJ, Forman-Kay JD.
Nat Struct Mol Biol. 2007 Aug;14(8):738-45. doi: 10.1038/nsmb1278. Epub 2007 Jul 29.
PMID: 17660831 Free PMC article.

Regulatory interaction between CFTR and the SLC26 transporters.
Shcheynikov N, Ko SB, Zeng W, Choi JY, Dorwart MR, Thomas PJ, Muallem S.
Novartis Found Symp. 2006;273:177-86; discussion 186-92, 261-4.
PMID: 17120768

Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3- secretion: relevance to cystic fibrosis.
Wang Y, Soyombo AA, Shcheynikov N, Zeng W, Dorwart M, Marino CR, Thomas PJ, Muallem S.
EMBO J. 2006 Nov 1;25(21):5049-57. doi: 10.1038/sj.emboj.7601387. Epub 2006 Oct 19.
PMID: 17053783 Free PMC article.

ATP binding and ATP hydrolysis play distinct roles in the function of 26S proteasome.
Liu CW, Li X, Thompson D, Wooding K, Chang TL, Tang Z, Yu H, Thomas PJ, DeMartino GN.
Mol Cell. 2006 Oct 6;24(1):39-50. doi: 10.1016/j.molcel.2006.08.025.
PMID: 17018291 Free PMC article.

Nucleotide binding domain interactions during the mechanochemical reaction cycle of ATP-binding cassette transporters.
Moody JE, Thomas PJ.
J Bioenerg Biomembr. 2005 Dec;37(6):475-9. doi: 10.1007/s10863-005-9494-8.
PMID: 16691486 Review.

Coupling modes and stoichiometry of Cl-/HCO3- exchange by slc26a3 and slc26a6.
Shcheynikov N, Wang Y, Park M, Ko SB, Dorwart M, Naruse S, Thomas PJ, Muallem S.
J Gen Physiol. 2006 May;127(5):511-24. doi: 10.1085/jgp.200509392. Epub 2006 Apr 10.
PMID: 16606687 Free PMC article.

Aggresome formation.
Corboy MJ, Thomas PJ, Wigley WC.
Methods Mol Biol. 2005;301:305-27. doi: 10.1385/1-59259-895-1:305.
PMID: 15917642

Recognition and processing of misfolded proteins by PA700, the 19S regulatory complex of the 26S proteasome.
Liu CW, Strickland E, Demartino GN, Thomas PJ.
Methods Mol Biol. 2005;301:71-81. doi: 10.1385/1-59259-895-1:071.
PMID: 15917627

A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease.
Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ.
J Biol Chem. 2005 Jun 17;280(24):22670-8. doi: 10.1074/jbc.M501508200. Epub 2005 Apr 19.
PMID: 15840579

Side chain and backbone contributions of Phe508 to CFTR folding.
Thibodeau PH, Brautigam CA, Machius M, Thomas PJ.
Nat Struct Mol Biol. 2005 Jan;12(1):10-6. doi: 10.1038/nsmb881. Epub 2004 Dec 26.
PMID: 15619636 Free PMC article.

Uncoupling retro-translocation and degradation in the ER-associated degradation of a soluble protein.
Lee RJ, Liu CW, Harty C, McCracken AA, Latterich M, Römisch K, DeMartino GN, Thomas PJ, Brodsky JL.
EMBO J. 2004 Jun 2;23(11):2206-15. doi: 10.1038/sj.emboj.7600232. Epub 2004 May 20.
PMID: 15152188 Free PMC article.

Gating of CFTR by the STAS domain of SLC26 transporters.
Ko SB, Zeng W, Dorwart MR, Luo X, Kim KH, Millen L, Goto H, Naruse S, Soyombo A, Thomas PJ, Muallem S.
Nat Cell Biol. 2004 Apr;6(4):343-50. doi: 10.1038/ncb1115. Epub 2004 Mar 28.
PMID: 15048129 Free PMC article.

Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-).
Shcheynikov N, Kim KH, Kim KM, Dorwart MR, Ko SB, Goto H, Naruse S, Thomas PJ, Muallem S.
J Biol Chem. 2004 May 21;279(21):21857-65. doi: 10.1074/jbc.M313323200. Epub 2004 Mar 9.
PMID: 15010471

Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator.
Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, Dorwart M, Fowler R, Gao X, Guggino WB, Hendrickson WA, Hunt JF, Kearins MC, Lorimer D, Maloney PC, Post KW, Rajashankar KR, Rutter ME, Sauder JM, Shriver S, Thibodeau PH, Thomas PJ, Zhang M, Zhao X, Emtage S.
EMBO J. 2004 Jan 28;23(2):282-93. doi: 10.1038/sj.emboj.7600040. Epub 2003 Dec 18.
PMID: 14685259 Free PMC article.

Organic solutes rescue the functional defect in delta F508 cystic fibrosis transmembrane conductance regulator.
Zhang XM, Wang XT, Yue H, Leung SW, Thibodeau PH, Thomas PJ, Guggino SE.
J Biol Chem. 2003 Dec 19;278(51):51232-42. doi: 10.1074/jbc.M309076200. Epub 2003 Oct 7.
PMID: 14532265

Assessment of protein folding/solubility in live cells.
Stidham RD, Wigley WC, Hunt JF, Thomas PJ.
Methods Mol Biol. 2003;205:155-69. doi: 10.1385/1-59259-301-1:155.
PMID: 12491885 No abstract available.

Endoproteolytic activity of the proteasome.
Liu CW, Corboy MJ, DeMartino GN, Thomas PJ.
Science. 2003 Jan 17;299(5605):408-11. doi: 10.1126/science.1079293. Epub 2002 Dec 12.
PMID: 12481023 Free PMC article.

A molecular mechanism for aberrant CFTR-dependent HCO(3)(-) transport in cystic fibrosis.
Ko SB, Shcheynikov N, Choi JY, Luo X, Ishibashi K, Thomas PJ, Kim JY, Kim KH, Lee MG, Naruse S, Muallem S.
EMBO J. 2002 Nov 1;21(21):5662-72. doi: 10.1093/emboj/cdf580.
PMID: 12411484 Free PMC article.

The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3.
Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I.
J Biol Chem. 2002 Dec 27;277(52):50503-9. doi: 10.1074/jbc.M201862200. Epub 2002 Oct 25.
PMID: 12403779

ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer.
Smith PC, Karpowich N, Millen L, Moody JE, Rosen J, Thomas PJ, Hunt JF.
Mol Cell. 2002 Jul;10(1):139-49. doi: 10.1016/s1097-2765(02)00576-2.
PMID: 12150914 Free PMC article.

Conformational remodeling of proteasomal substrates by PA700, the 19 S regulatory complex of the 26 S proteasome.
Liu CW, Millen L, Roman TB, Xiong H, Gilbert HF, Noiva R, DeMartino GN, Thomas PJ.
J Biol Chem. 2002 Jul 26;277(30):26815-20. doi: 10.1074/jbc.M201782200. Epub 2002 May 14.
PMID: 12011044

Cooperative, ATP-dependent association of the nucleotide binding cassettes during the catalytic cycle of ATP-binding cassette transporters.
Moody JE, Millen L, Binns D, Hunt JF, Thomas PJ.
J Biol Chem. 2002 Jun 14;277(24):21111-4. doi: 10.1074/jbc.C200228200. Epub 2002 Apr 18.
PMID: 11964392 Free PMC article.

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