dibasic amino acid
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2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.



Author(s):  
Aude Servais ◽  
Bertrand Knebelmann

Cystinuria (OMIM #220100) is an autosomal recessive disorder of a dibasic amino acid transport in the apical membrane of epithelial cells of the renal proximal tubule and small intestine. It leads to increased urinary cystine excretion and recurrent urolithiasis. The cystine transporter is an heterodimeric transporter which is composed of a heavy subunit, rBAT, linked to a light subunit, b0,+AT. Two genes, SLC3A1 (solute carrier family 3 member 1) and SLC7A9, coding for rBAT and b0,+AT, account for the genetic basis of cystinuria. Cystinuria may lead to obstruction, infections, and ultimately to renal insufficiency. The diagnosis of cystinuria mainly relies on stone analysis, urinary cystine measurement, or urinary cystine crystal identification. Medical treatment is based upon a stepwise strategy using hydration and alkalinization as basic measures, with the addition of thiol derivatives in refractory cases. Urological interventions are often indicated for the management of cystine stones >5 mm in diameter.



2013 ◽  
Vol 305 (12) ◽  
pp. F1645-F1655 ◽  
Author(s):  
Andrea Di Giacopo ◽  
Isabel Rubio-Aliaga ◽  
Alessandra Cantone ◽  
Ferruh Artunc ◽  
Rexhep Rexhepaj ◽  
...  

Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 ( rBAT) and SLC7A9 ( b 0,+ AT). Gene targeting of the catalytic subunit ( Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b0,+. No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b0,+AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.





2004 ◽  
Vol 377 (3) ◽  
pp. 607-616 ◽  
Author(s):  
Mikiko ITO ◽  
Sachi IIDAWA ◽  
Michiyo IZUKA ◽  
Sakiko HAITO ◽  
Hiroko SEGAWA ◽  
...  

Treatment with PTH (parathyroid hormone) or a high-Pi diet causes internalization of the type IIa sodium-dependent phosphate (Na/Pi IIa) co-transporter from the apical membrane and its degradation in the lysosome. A dibasic amino acid motif (KR) in the third intracellular loop of the co-transporter is essential for protein's PTH-induced retrieval. To elucidate the mechanism of internalization of Na/Pi IIa, we identified the interacting protein for the endocytic motif by yeast two-hybrid screening. We found a strong interaction of the Na/Pi IIa co-transporter with a small protein known as the PEX19 (human peroxisomal farnesylated protein; PxF, Pex19p). PEX19 can bind to the KR motif, but not to a mutant with this motif replaced with NI residues. PEX19 is highly expressed in mouse and rat kidney. Western blot analysis indicates that PEX19 is located in the cytosolic and brush-border membrane fractions (microvilli and the subapical component). Overexpression of PEX19 stimulated the endocytosis of the Na/Pi IIa co-transporter in opossum kidney cells in the absence of PTH. In conclusion, the present study indicates that PEX19 may be actively involved in controlling the internalization and trafficking of the Na/Pi IIa co-transporter.



2003 ◽  
Vol 171 (3) ◽  
pp. 1304-1311 ◽  
Author(s):  
Loren C. Denlinger ◽  
Julie A. Sommer ◽  
Karen Parker ◽  
Lalitha Gudipaty ◽  
Philip L. Fisette ◽  
...  


2002 ◽  
Vol 50 (8) ◽  
pp. 1023-1030 ◽  
Author(s):  
Guida Maria Portela–GomesM ◽  
Mats Stridsberg

Chromogranin (Cg) B is an acidic glycoprotein present in neuroendocrine tissue. The sequence shows several dibasic amino acid positions susceptible to proteolytic cleavage. The purpose of this study was to elucidate the expression of CgB epitopes in the human endocrine pancreas. Tissue sections of six human pancreata were immunostained with 16 different region-specific antibodies to the CgB molecule, using double immunofluorescence techniques. The CgB epitope pattern varied in the four major islet cell types. B (insulin)-cells expressed immunoreactivity to all region-specific antibodies. The antibodies to the N-terminal and mid-portions of CgB showed moderate immunoreactivity, the C-terminal antibodies weak. A (glucagon)-cells were reactive only to the N-terminal and mid-portion antibodies but, after microwave pretreatment, to all antibodies, whereas D (somatostatin)-cells expressed only the sequence CgB 244–255 and a subpopulation CgB 580–595. PP (pancreatic polypeptide) cells were immunostained with antibodies between CgB 1–417 and a few with CgB 580–593. The fragment CgB 244–255 was expressed in all four cell types. The cause of these differences may be cell-specific cleavage or masking of the molecule, but varying translation of CgB mRNA is also possible. The extent to which these epitopes reflect fragments having biological functions remains to be evaluated.



1999 ◽  
Vol 10 (12) ◽  
pp. 4135-4147 ◽  
Author(s):  
Rahel Pfeiffer ◽  
Jan Loffing ◽  
Grégoire Rossier ◽  
Christian Bauch ◽  
Christian Meier ◽  
...  

Mutations of the glycoprotein rBAT cause cystinuria type I, an autosomal recessive failure of dibasic amino acid transport (b0,+ type) across luminal membranes of intestine and kidney cells. Here we identify the permease-like protein b0,+AT as the catalytic subunit that associates by a disulfide bond with rBAT to form a hetero-oligomeric b0,+amino acid transporter complex. We demonstrate its b0,+-type amino acid transport kinetics using a heterodimeric fusion construct and show its luminal brush border localization in kidney proximal tubule. These biochemical, transport, and localization characteristics as well as the chromosomal localization on 19q support the notion that the b0,+AT protein is the product of the gene defective in non-type I cystinuria.



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