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Research Programmes

Molecular Medicine

Molecular pathology and therapy in heterogenic and multigenic diseases

Manuel Palacín

Manuel Palacín

Group Leader
Professor (Biochemistry and Molecular Biology Dept. - UB)

Office Tel : +34 93 403 71 99
Lab Tel : +34 93 403 47 01 / +34 93 403 71 98 / +34 93 403 71 97
e-mail : manuel.palacinirbbarcelona.org

Background

One of the functions of the kidney is the tubular re-absorption of solutes, like amino acids, filtrated in the glomerulus. Several amino acid transporters are involved in this process. Primary inherited aminoacidurias (PIA) are caused by defects in several of these transporters. Over the last ten years studies on PIA have uncovered part of the molecular bases of renal reabsorption of amino acids. The tranporters involved in cystinuria, lysinuric protein intolerance and in most patients with Hartnup disorder have been identified. In contrast, those responsible for isolated cystinuria, autosomal dominant hyperdibasic aminoaciduria type I, isolated lysinuria, renal familial iminoglycinuria, dicarboxylic aminoaciduria and Hartnup disorder in some patients remain elusive.

Heteromeric amino acid transporters (HATs) are composed of a heavy subunit and a light subunit. These are unique features among mammalian plasma membrane amino acid transporters. Two homologous heavy subunits from the SLC3 family have been cloned, rBAT (i.e., related to b0,+ amino acid transport) and 4F2hc (i.e., heavy chain of the surface antigen 4F2hc, also named CD98 or fusion regulatory protein 1 (FRP1). Ten light subunits (SLC7 family members from SLC7A5 to SLC7A14) have been identified. Six of these are partners of 4F2hc (LAT1, LAT2, y+LAT1, y+LAT2, asc1, and xCT); one forms a heterodimer with rBAT (b0,+AT); two (asc2 and AGT-1) appear to interact with as yet unknown heavy subunits; and the last one (arpAT) may interact with rBAT, 4F2hc or an unidentified heavy subunit. Two light subunits are not present in humans: asc2 is not found in the genome sequence and arpAT is heavily inactivated in this genome.

Research Interests

The general objective of our group is to determine the molecular mechanisms involved in renal re-absorption and intestinal absorption of amino acids. This general objective is structured into three levels:

  1. Identification of the amino acid transporters involved in the re-absorption of amino acids and those responsible for the development of inherited aminoacidurias. Description of the molecular mechanisms underlying the loss of transport functions of the amino acid transporters, due to disease-causing mutations.
  2. Structural and structure-function relationship studies of Heteromeric Amino Acid Transporters.
  3. Structure-function relationship studies of the tumorigenic role of the multifunctional protein 4F2hc.
Research Lines

To achieve our objectives, our group is structured around 3 research lines.

1. Identification of the amino acid transporters involved in re-absorption of amino acids and those responsible for the development of inherited aminoacidurias.

Our laboratory reported the seminal observations that led to the identification of a new family of amino acid transporters, the Heteromeric Amino acid Transporters (HATs), with the cloning of rBAT and the functional identification of 4F2hc as ancillary proteins of these transporters. Moreover, we have identified five of the ten light subunits of HATs (b0,+AT, y+LAT1, y+LAT2, LAT2 and ArpAT). Three of these transporters are involved in renal re-absorption of amino acids: i) System b0,+ (rBAT/bo,+AT), responsible for apical re-absorption of dibasic amino acids and cystine. ii) System y+L (4F2hc/y+LAT1), responsible for the basolateral efflux of dibasic amino acids. iii) System L (4F2hc/LAT2), responsible for the basolateral efflux of several neutral amino acids, including cysteine. We have also identified the amino acid transporters that are defective in cystinuria (rBAT/b0,+AT) and lysinuric protein intolerance (4F2hc/y+LAT1). At present, we are studying the physiology of basolateral transporters that are candidates to play a role in renal re-absorption of amino acids and inherited aminoacidurias. Moreover, we are generating mouse models defective in renal re-absorption-related transporters. Indeed, the b0,+AT null knock-out mouse parallels human cystinuria, including cystinuria lithiasis. This model is currently being used to identify new anti-lithiasic drugs.

2. Structural and structure-function relationship studies of Heteromeric Amino Acid Transporters.

We have demonstrated that the light subunit of HATs is the catalytic part of the HAT transporters. Using transporter xCT as a model for the light subunits of HATs, we have delineated the membrane topology of these transporters and identified several relevant residues for their transport activity. Moreover, we have solved the structure of the ectodomain of the heavy chain 4F2hc at a resolution of 2.1 Å. We are currently addressing the atomic structure of HATs by means of several strategies, including the study of prokaryotic homologues of the light subunits.

3. Structure-function relationship studies of the tumorigenic role of the multifunctional protein 4F2hc.

4F2hc (also named CD98) is a multifunctional protein involved in amino acid transport, cell fusion and integrin activation. Moreover, 4F2hc has tumorigenic activity. On the basis of the atomic structure of the ectodomain of this protein, we are currently studying its potential glucosidase and/or lectin activities and also protein interactions of this ectodomain.

Funding

This group receives financial support from the following sources:

  • Fundació La Caixa ("La Caixa" Foundation)
  • Ministerio de Educación y Ciencia (Spanish Ministry of Science and Education)
  • European Commission
  • Generalitat de Catalunya (Government of Catalonia)
  • Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (Spanish National Institute of Health)
  • Fundació La Marató-TV3 ("La Marató TV3" Foundation)
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Core facilities and Services Directory

  • Generalitat de catalunya
  • Generalitat de catalunya. Salut
  • Universidad de Barcelona
  • Parc cientific

Institute for Research in Biomedicine (IRB Barcelona)
Parc Científic de Barcelona
C/ Baldiri Reixac 10
08028 Barcelona - Spain
Tel: +34 93 402 02 50 | Fax: +34 93 403 71 14
infoarrobairbbarcelona.org