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-Structure paper
タイトル | Structural basis for substrate specificity of heteromeric transporters of neutral amino acids. |
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ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 118, Issue 49, Year 2021 |
掲載日 | 2021年12月7日 |
![]() | Carlos F Rodriguez / Paloma Escudero-Bravo / Lucía Díaz / Paola Bartoccioni / Carmen García-Martín / Joan G Gilabert / Jasminka Boskovic / Víctor Guallar / Ekaitz Errasti-Murugarren / Oscar Llorca / Manuel Palacín / ![]() |
PubMed 要旨 | Despite having similar structures, each member of the heteromeric amino acid transporter (HAT) family shows exquisite preference for the exchange of certain amino acids. Substrate specificity ...Despite having similar structures, each member of the heteromeric amino acid transporter (HAT) family shows exquisite preference for the exchange of certain amino acids. Substrate specificity determines the physiological function of each HAT and their role in human diseases. However, HAT transport preference for some amino acids over others is not yet fully understood. Using cryo-electron microscopy of apo human LAT2/CD98hc and a multidisciplinary approach, we elucidate key molecular determinants governing neutral amino acid specificity in HATs. A few residues in the substrate-binding pocket determine substrate preference. Here, we describe mutations that interconvert the substrate profiles of LAT2/CD98hc, LAT1/CD98hc, and Asc1/CD98hc. In addition, a region far from the substrate-binding pocket critically influences the conformation of the substrate-binding site and substrate preference. This region accumulates mutations that alter substrate specificity and cause hearing loss and cataracts. Here, we uncover molecular mechanisms governing substrate specificity within the HAT family of neutral amino acid transporters and provide the structural bases for mutations in LAT2/CD98hc that alter substrate specificity and that are associated with several pathologies. |
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手法 | EM (単粒子) |
解像度 | 3.98 Å |
構造データ | EMDB-11952, PDB-7b00: |
化合物 | ![]() ChemComp-AJP: |
由来 |
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![]() | MEMBRANE PROTEIN / HATs / amino-acid / transporter / membrane / protein / heterodimer |