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• Differential cystine and dibasic amino acid handling after loss of function of the
Most relevant
amino acid transporter b0,+AT (Slc7a9) in mice. di GiacoPo a, rubio-aliaGa i, cantone
scientific a, a F, r r, F-W i, F-l M, G n, s G, J i,
rtunceXhePaJreyaGnerontlitJósehrinGtanGeaenecke
Mohebbi n, closs ei, Palacín M, nunes V, daniel h, lanG F, caPasso G, WaGner ca. Am J
articles

Physiol Renal Physiol. 2013 Dec 15;305(12):F1645-55.

• Mfn2 modulates the UPR and mitochondrial function via repression of PERK. Muñoz
JP, iVanoVa s, sánchez-WandelMer J, Martínez-cristóbal P, noGuera e, sancho a, díaz-

raMos a, hernández-alVarez Mi, sebastián d, MauVezin c, Palacín M, zorzano a. EMBO J.
2013 Aug 28;32(17):2348-61.

• The SLC3 and SLC7 families of amino acid transporters. F d, k y, P M.
otiadisanaialacín
Mol Aspects Med. 2013 Apr-Jun;34(2-3):139-58.

• The small SLC43 family: facilitator system l amino acid transporters and the orphan
EEG1. b s, F d, s c, k y, P M. Mol Aspects Med. 2013 Apr-
odoyotiadistoeGeranaialacín
Jun;34(2-3):638-45. doi: 10.1016/j.mam.2012.12.006.
áó

• Expression of human heteromeric amino acid transporters in the yeast Pichia pasto-

ris. costa M, rosell a, álVarez-MariMon e, zorzano a, Fotiadis d, Palacín M. Protein Expr
Purif. 2013 Jan;87(1):35-40.
ó

Our most relevant result related to rare diseases during 2013 has been the genera- ó
Highlights
tion of the first structural model of a human Heteromeric Amino acid Transporter

(HAT). In 2013 we reported the expression of human HATs in the yeast Pichia (ar-
ticle 5 in the previous section). This was the base to obtain purified human 4F2hc/ í

LAT2, which allowed negative-staining electron microscopy studies that rendered
a model of the heterodimer at 21 Å resolution. Docking analysis and biochemical Áó

crosslinking experiments refined and confirmed the model. Our results showed that

the ectodomain of the heavy subunit 4F2hc almost completely covers the external
face of the light subunit and increases its stability. This model is at present the

structural paradigm of two transporters (rBAT/b0,+AT and 4F2hc/y+LAT1) which

mutations cause aminoacidurias (cystinurias type A and B and isolated cystinuria,
and lysinuric protein intolerance; LPI). These results have been publish beginning

of 2014 ((Rosell A, Meury M, lvarez-Marimon E, Costa M, Pérez-Cano L, Zorzano A,
Fernndez-Recio J, Palacn M, Fotiadis D (2014) Proc Natl Acad Sci U S A. 111:2966-

71). This research has been supported by EDICT (7FP.Health-2007-2.1.1-5 Grant

Agreement: 201924) and SAF 2012-40080 (MICINN). Our leadership on structural
studies of HATs facilitated to obtain financial support to solve the atomic structure

of bacterial homologues of the transporter mutated in LPI (4F2hc/y+LAT1) (Fun-

dacin Ramn Areces and to develop 4F2hc/xCT inhibitors, a therapeutic target in
gliomas (Fundaci La Marat-TV3 ).

In a collaborative study with different CIBERER units we have obtained for the first
13
time expression in bacteria and purification of human BCKDK, main protein control- í20
ling oxidation of branched-chain amino acids. This preparation allowed the deter- T
OR
mination of the residual kinase activity of mutants causing a new neurobehavioral P
RE
deficit. This study has been published at beginning of 2014 (Garca-Cazorla A et al. L
Hum Mutat. 2014 Apr;35(4):470-7).
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