Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter
Por:
Rullo-Tubau J, Martinez-Molledo M, Bartoccioni P, Puch-Giner I, Arias AY, Saen-Oon S, Stephan-Otto Attolini C, Artuch-Iriberri R, Díaz L, Guallar V, Errasti-Murugarren E, Palacín M and Llorca O
Publicada:
6 abr 2024
Ahead of Print:
6 abr 2024
Resumen:
Recent cryoEM studies elucidated details of the structural basis for the substrate selectivity and translocation of heteromeric amino acid transporters. However, Asc1/CD98hc is the only neutral heteromeric amino acid transporter that can function through facilitated diffusion, and the only one that efficiently transports glycine and D-serine, and thus has a regulatory role in the central nervous system. Here we use cryoEM, ligand-binding simulations, mutagenesis, transport assays, and molecular dynamics to define human Asc1/CD98hc determinants for substrate specificity and gain insights into the mechanisms that govern substrate translocation by exchange and facilitated diffusion. The cryoEM structure of Asc1/CD98hc is determined at 3.4-3.8 angstrom resolution, revealing an inward-facing semi-occluded conformation. We find that Ser 246 and Tyr 333 are essential for Asc1/CD98hc substrate selectivity and for the exchange and facilitated diffusion modes of transport. Taken together, these results reveal the structural bases for ligand binding and transport features specific to human Asc1.
Asc1/CD98hc is a key regulator of small neutral amino acid transport in the brain and adipose tissue. Here, authors report the structure of semi-occluded hAsc1/CD98hc and provide a model for Asc1 exchange and facilitated diffusion modes of transport.
Filiaciones:
Rullo-Tubau J:
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, E-08028, Barcelona, Spain
Martinez-Molledo M:
Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, E-28029, Madrid, Spain
Bartoccioni P:
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, E-08028, Barcelona, Spain
The Spanish Center of Rare Diseases (CIBERER U-731), Baldiri Reixac 10, E-08028, Barcelona, Spain
Puch-Giner I:
Electronic and atomic protein modelling group, Barcelona Supercomputing Center, Plaça d'Eusebi Güell, 1-3, E-08034, Barcelona, Spain
Arias AY:
Clinical Biochemistry Department, Sant Joan de Déu Research Institute, Pg. de Sant Joan de Déu, 2, E-08950, Esplugues de Llobregat, Spain
Saen-Oon S:
Nostrum Biodiscovery, Av. de Josep Tarradellas, 8-10, E-08029, Barcelona, Spain
Stephan-Otto Attolini C:
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, E-08028, Barcelona, Spain
Artuch-Iriberri R:
The Spanish Center of Rare Diseases (CIBERER U-731), Baldiri Reixac 10, E-08028, Barcelona, Spain
Clinical Biochemistry Department, Sant Joan de Déu Research Institute, Pg. de Sant Joan de Déu, 2, E-08950, Esplugues de Llobregat, Spain
Díaz L:
Nostrum Biodiscovery, Av. de Josep Tarradellas, 8-10, E-08029, Barcelona, Spain
Guallar V:
Electronic and atomic protein modelling group, Barcelona Supercomputing Center, Plaça d'Eusebi Güell, 1-3, E-08034, Barcelona, Spain
Nostrum Biodiscovery, Av. de Josep Tarradellas, 8-10, E-08029, Barcelona, Spain
Errasti-Murugarren E:
The Spanish Center of Rare Diseases (CIBERER U-731), Baldiri Reixac 10, E-08028, Barcelona, Spain
Physiological Sciences Department, Genetics Area, School of Medicine and Health Sciences, University of Barcelona, Bellvitge Campus. Feixa Llarga s/n, E-08907, L'Hospitalet de Llobregat, Spain
Human Molecular Genetics Laboratory, Gene, Disease and Therapy Program, IDIBELL, Hospital Duran i Reynals, Avd. Gran Via de L'Hospitalet 199, E-08908, L'Hospitalet de Llobregat, Spain
Palacín M:
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, E-08028, Barcelona, Spain
The Spanish Center of Rare Diseases (CIBERER U-731), Baldiri Reixac 10, E-08028, Barcelona, Spain
Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Av. Diagonal, 643, E-08028, Barcelona, Spain
Llorca O:
Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro, 3, E-28029, Madrid, Spain
Green Submitted, gold
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