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


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.

SUBMITTER: Chiduza GN 

PROVIDER: S-EPMC7285653 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Chiduza George N GN   Johnson Rachel M RM   Wright Gareth S A GSA   Antonyuk Svetlana V SV   Muench Stephen P SP   Hasnain S Samar SS  

Acta crystallographica. Section D, Structural biology 20190628 Pt 7


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 confo  ...[more]

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