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A novel digestive complex and its role in Hartnup disorder: trafficking of the neutral amino acid transporter B0AT1 by angiotensin converting enzyme 2 (ACE2)

S. Kowalczuk,1 A. Bröer,1 N. Tietze,1 J.M. Vanslambrouck,2 J.E.J. Rasko2,3 and S. Bröer,1 1School of Biochemistry and Molecular Biology, Australian National University, Canberra, ACT 0200, Australia, 2Gene and Stem Cell Therapy Program, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW 2050, Australia and 3Cell and Molecular Therapies, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.

In the intestine, proteins are digested by proteases and brush-border peptidases into small peptides and amino acids, which are then absorbed by peptide and amino acid transporters. Neutral amino acids are absorbed by the amino acid transporter B0AT1. B0AT1 is also expressed in the kidney, where it mediates reabsorption of neutral amino acids from the primary urine. Mutations in B0AT1 cause Hartnup disorder, a defect in neutral amino acid transport resulting in neutral aminoaciduria.

In the kidney, B0AT1 requires the auxiliary protein collectrin for trafficking to the brush-border membrane. However, collectrin is not expressed in the intestine, suggesting that a different protein facilitates B0AT1 trafficking in this tissue. Interestingly, the closest homologue of collectrin is a brush-border carboxypeptidase, angiotensin converting enzyme 2 (ACE2).

Coexpression of B0AT1 and ACE2 in Xenopus laevis oocytes* caused a dramatic increase in the surface expression of B0AT1. Addition of a peptide containing a carboxyterminal leucine residue to these oocytes resulted in leucine transport by B0AT1, demonstrating that B0AT1 and ACE2 form a complex that performs two consecutive steps in protein digestion and absorption. The Hartnup disorder associated mutations B0AT1 (D173N) and B0AT1 (R240Q) showed reduced interaction with both ACE2 and collectrin, thereby explaining how these mutations cause Hartnup disorder.


*Xenopus laevis oocytes were harvested by surgery of anaesthesized frogs (MS-222, 1.5g/l). The procedure was approved by the Animal Experimentation Ethics Committee of the Australian National University.