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LAT1 (SLC7A5) and CD98hc (SLC3A2) complex dynamics revealed by single-particle cryo-EM

DOI: 10.1107/S2059798319009094 DOI Help

Authors: George N. Chiduza (University of Liverpool) , Rachel M. Johnson (University of Leeds) , Gareth S. A. Wright (University of Liverpool) , Svetlana V. Antonyuk (University of Liverpool) , Stephen P. Muench (University of Leeds) , S. Samar Hasnain (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section D Structural Biology , VOL 75 , PAGES 660 - 669

State: Published (Approved)
Published: July 2019
Diamond Proposal Number(s): 15262

Open Access Open Access

Abstract: Solute carriers are a large class of transporters that play key roles in normal and disease physiology. Among the solute carriers, heteromeric amino-acid transporters (HATs) are unique in their quaternary structure. LAT1–CD98hc, a HAT, transports essential amino acids and drugs across the blood–brain barrier and into cancer cells. It is therefore an important target both biologically and therapeutically. During the course of this work, cryo-EM structures of LAT1–CD98hc in the inward-facing conformation and in either the substrate-bound or apo states were reported to 3.3–3.5 Å resolution [Yan et al. (2019), Nature (London), 568, 127–130]. Here, these structures are analyzed together with our lower resolution cryo-EM structure, and multibody 3D auto-refinement against single-particle cryo-EM data was used to characterize the dynamics of the interaction of CD98hc and LAT1. It is shown that the CD98hc ectodomain and the LAT1 extracellular surface share no substantial interface. This allows the CD98hc ectodomain to have a high degree of movement within the extracellular space. The functional implications of these aspects are discussed together with the structure determination.

Journal Keywords: transporters; cryo-EM; amino-acid transporters; solute carriers; LAT1; CD98hc; SLC7A5; SLC3A2

Subject Areas: Biology and Bio-materials

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