John Riordan, PhD

RIORDAN - John Michael Hooker Distinguished Professor of Biochemistry & Biophysics

PHD - University of Toronto

RESEARCH

Structure, Function And Biosynthetic Processing Of Membrane Proteins

The primary research focus is the structure, function and biosynthetic processing of membrane proteins which provide permeability pathways through the membranes of cells. Much of the current work is concentrated on the ion channel protein which is absent or dysfunctional in patients with cystic fibrosis. All patients have mutations in the gene which codes for this protein which is called CFTR (cystic fibrosis transmembrane conductance regulator).

CFTR is a secretory channel which plays a central role in maintaining fluid balance in several tissues including the lung airways, the intestines and many exocrine glands such as the pancreas and salivary glands. To elucidate the molecular mechanisms of CFTR function, we study the single channel properties by electrophysiological techniques. The enzymatic activity is studied after purification of the recombinant protein generated in different cultured cell systems. Isolation of the molecule by single step methods employing antibodies and other manipulations also enables investigation of CFTR's interaction with other cellular molecules. A major objective of studies with the purified molecule is to obtain 3-dimensional structure information so that small molecules capable of recognizing features of its surface shape can be synthesized and used to modulate its folding and activity. CFTR interaction partners important in its function and biosynthesis are being identified by proteomic methods.

REPRESENTATIVE PUBLICATIONS pubmed.png (click for Full Publication List)

  • He L, Kota P, Aleksandrov AA, Cui L, Jensen T, Dokholyan NV, Riordan JR. Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. FASEB J. 2013 Feb;27(2):536-45.
  • Aleksandrov AA, Kota P, Cui L, Jensen T, Alekseev AE, Reyes S, He L, Gentzsch M, Aleksandrov LA, Dokholyan NV, Riordan JR. Allosteric modulation balances thermodynamic stability and restores function of ΔF508 CFTR. J Mol Biol. 2012 May 25; 419(1-2):41-60.
  • Clunes LA, Davies CM, Coakley RD, Aleksandrov AA, Henderson AG, Zeman KL, Worthington EN, Gentzsch M, Kreda SM, Cholon D, Bennett WD, Riordan JR, Boucher RC, Tarran R. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. FASEB J. 2012 Feb;26(2):533-45.
  • Rosenberg MF, O'Ryan LP, Hughes G, Zhao Z, Aleksandrov LA, Riordan JR, Ford RC. The cystic fibrosis transmembrane conductance regulator (CFTR): three-dimensional structure and localization of a channel gate. J Biol Chem. 2011 Dec; 286(49):42647-54.
  • Malmberg EK, Pelaseyed T, Petersson A, Seidler UE, de Jonge H, Riordan JR, Hansson GC. The transmembrane MUC17 mucin C-terminus binds to the scaffold protein PDZK1 that stably localizes it to the enterocyte apical membrane in the small intestine. Biochem J. 2007 Nov 8
  • Pathak AK, Pathak V, Riordan JR, Suling WJ, Gurcha SS, Besra GS, Reynolds RC. Synthesis of symmetrical C- and pseudo-symmetrical O-linked disaccharide analogs for arabinosyltransferase inhibitory activity in Mycobacterium tuberculosis. Bioorg Med Chem Lett. 2007 Aug 15;17(16):4527-30. Epub 2007
  • Gentzsch M, Choudhury A, Chang XB, Pagano RE, Riordan JR. Misassembled mutant DeltaF508 CFTR in the distal secretory pathway alters cellular lipid trafficking. J Cell Sci. 2007 Feb 1;120(Pt 3):447-55. Epub 2007
  • Cui L, Aleksandrov L, Chang XB, Hou YX, He L, Hegedus T, Gentzsch M, Aleksandrov A, Balch WE, Riordan JR. Domain interdependence in the biosynthetic assembly of CFTR. J Mol Biol. 2007 Jan 26;365(4):981-94. Epub 2006
  • Wang X, Venable J, LaPointe P, Hutt DM, Koulov AV, Coppinger J, Gurkan C, Kellner W, Matteson J, Plutner H, Riordan JR, Kelly JW, Yates JR 3rd, Balch WE. Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell. 2006 Nov 17;127(4):803-15
  • Aleksandrov AA, Aleksandrov LA, Riordan JR. CFTR (ABCC7) is a hydrolyzable-ligand-gated channel. Pflugers Arch. 2007 Feb;453(5):693-702. Epub 2006
  • Hegedus T, Aleksandrov A, Cui L, Gentzsch M, Chang XB, Riordan JR. F508del CFTR with two altered RXR motifs escapes from ER quality control but its channel activity is thermally sensitive. Biochim Biophys Acta. 2006 May;1758(5):565-72. Epub 2006
  • Cui L, Aleksandrov L, Hou YX, Gentzsch M, Chen JH, Riordan JR, Aleksandrov AA. The role of cystic fibrosis transmembrane conductance regulator phenylalanine 508 side chain in ion channel gating. J Physiol. 2006 Apr 15;572(Pt 2):347-58. Epub 2006

        CONTACT INFORMATION

        6107 Thurston-Bowles
        Campus Box 7248
        Chapel Hill, NC 27599


        Office: 919-843-4751
        john_riordan@med.unc.edu

        Lab Rooms: 6107 Thurston-Bowles
        Lab Phone: 919-966-0329