Reinhart Reithmeier Professor

B.Sc., Carleton University, 1972
Ph.D., University of British Columbia, 1977
Harvard University, 1976-78
University of Toronto, 1978-80
University of Alberta, 1980-86
CNRS, Universite de Nice, France, 1992-93
Blood Research, University of British Columbia, 2009

Medical Sciences Building, Room 5242
416-978-7739
r.reithmeier@utoronto.ca


Structure and Function of Membrane Proteins

Member of the following Training Programs of interest to students and PDF's:
CIHR Training Program: Protein Folding and Interaction Dynamics




Research Synopsis

 


My laboratory is interested in the structure and function of membrane proteins, in particular the chloride/bicarbonate anion exchanger (AE1, Band 3). The Band 3 glycoprotein of the erythrocyte membrane is responsible for the exchange of chloride and bicarbonate across the plasma membrane, a process necessary for respiration. A truncated form of the protein (kAE1) is expressed in the kidney where it plays an essential role in bicarbonate re-absorption.
   

Proposed folding of AE1.

A
major aim of our research is to determine, at the molecular level, the mechanism of action of the human chloride/bicarbonate anion exchanger (AE1) and a truncated version kAE1, expressed in the kidney. We are also interested in determining the effect of mutations in the AE1 (SLC4A1) gene, linked to various hematological and kidney diseases, on the biosynthesis and function of the protein. A wide variety of structural, cellular and molecular biological techniques are employed in our research.

We have grown small 3-dimensional crystals and 2-dimensional arrays of the human Band 3 protein and we are determining its structure by X-ray diffraction and electron microscopy. A Band 3 homologue identified in yeast is being characterized with the aim of determining its structure. The structure of the cytosolic domain of normal and mutant kAE1, expressed in E. coli , is also being studied using various biophysical techniques. We are also working on the expression and crystallization of bacterial anion transporters (SLC26A/SulP) related to AE1.

We are studying the effects of mutations in Band 3 on biosynthesis and folding of this membrane protein using cell-free systems and transfected cells. We are particularly interested in the role of chaperones in mediating the proper folding and trafficking of this membrane protein. The interaction of Band 3 with glycophorin A, carbonic anhydrase, cytoskeletal and other cytosolic proteins is also a current interest. One goal is to identify the AE1 interactome, the full complement of interacting proteins using proteomics and membrane yeast 2-hybrid methods.

The interactions between various transmembrane segments in Band 3 and with the lipid bilayer is being simulated by computer modeling. Basic principles of membrane protein structure are being established by analyses of the amino acid sequences in membrane protein data banks.
 
   


Selected Publications

Invited Chapters and Reviews

Yenchitomanus, P., Kittanakom, S., Rungroj, N., Cordat, E. and Reithmeier, R.A. F. (2005) Molecular mechanisms of autosomal dominant and recessive distal renal tubular acidosis caused by SLC4A1 mutations. J. Mol. Gen. Medicine 1 , 49-62.

Cheung, J.C. and Reithmeier, R.A.F. (2007) Scanning N-glycosylation mutagenesis of membrane proteins. Methods 41 , 451-459.

Peer-reviewed Journal Articles


Cordat, E., Kittanakom, S. Yenchitsomanus, P., Li, J. Du, K., Lukacs, G.L. and Reithmeier, R.A.F. (2006) Dominant and recessive distal renal acidosis mutations of the human kidney anion exchanger 1 induce distinct trafficking defects in epithelial cells. Traffic 7 , 117-128.

Bustos, S.P. and Reithmeier R.A.F. (2006) Structure and stability of hereditary spherocytosis mutants of the cytosolic domain of the erythrocyte anion exchanger 1 protein. Biochemistry 45 , 1026-1034.

Cordat, E. and Reithmeier R.A.F. (2006) Expression and interaction of two compound heterozygous distal renal tubular acidosis mutants of kidney anion exchanger 1 in epithelial cells. Am. J. Physiol . 291 , F1354-F1361.

Keskanokwong, T., Shandro, H.J., Kittanakom, S., Reithmeier, R.A.F., Akkarapatumwong, V., Yenchitsomanus, P. and Casey, J.R. (2007) Interaction of integrin-linked kinase with the kidney Cl - /HCO 3 - anion exchanger 1. J. Biol. Chem . 282, 23205-18.

Kittanakom, S., Cordat, E. and Reithmeier, R.A.F. (2008) Dominant-negative effect of Southeast Asian ovalocytosis anion exchanger 1 in compound heterozygous distal renal tubular acidosis. Biochem. J. 410, 271-281.

Pang, A.J., Bustos, S.P. and Reithmeier, R.A.F. (2008) Structural characterization of the cytosolic domain of kidney chloride/bicarbonate anion exchanger 1. Biochemistry 47, 4510-4517.

Patterson, S.T., Li, J., Kang, J.A., Wickrema, A., Williams, D.B., Reithmeier, R.A.F. (2009) Loss of specific chaperones involved in membrane glycoprotein biosynthesis during the maturation of human erythroid progenitor cells. J. Biol. Chem . 284 , 14547-57.

Ungsupravate, D. Sawasdee, N., Khositseth, S., Udomchaiprasertkul, W., Khoprasert, S., Li, J., Reithmeier, R.A.F., Yenchitsomanus, P.T. (2010) Impaired trafficking and intracellular retention of mutant kidney anion exchanger 1 proteins (G701D and A858D) associated with distal renal tubular acidosis. Mol. Membr. Biol 27 , 92-103.

Patterson, S.T., Reithmeier, R.A.F. (2010) Cell surface rescue of kidney anion exchanger 1 by disruption of chaperone interactions. J. Biol. Chem . 285, 33423-34.

Babu, M., Greenblatt, J.F., Emili, A., Strynadka, N.C., Reithmeier, R.A.F., Moraes, T.F. (2010) Structure of a SLC26 anion transporter STAS domain in complex with acyl carrier protein: implications for E. coli YchM in fatty acid metabolism. Structure 18, 1450-62.

Bustos, S. P, Reithmeier, R.A.F. (2011) Protein 4.2 interaction with hereditary spherocytosis mutants of the cytoplasmic domain of human anion exchanger 1 Biochem J 433, 313-322.

   

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