RESEARCH INTERESTS:
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. RECENT PUBLICATIONS:
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 |
Biochemistry and Biophysics - UNC School of Medicine
