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Evolutionary balance between foldability and functionality of a glucose transporter

Cited 10 time in Web of Science Cited 12 time in Scopus
Authors

Choi, Hyun-Kyu; Kang, Hyunook; Lee, Chanwoo; Kim, Hyun Gyu; Phillips, Ben P.; Park, Soohyung; Tumescheit, Charlotte; Kim, Sang Ah; Lee, Hansol; Roh, Soung-Hun; Hong, Heedeok; Steinegger, Martin; Im, Wonpil; Miller, Elizabeth A.; Choi, Hee-Jung; Yoon, Tae Young

Issue Date
2022-07
Publisher
Nature Publishing Group
Citation
Nature Chemical Biology, Vol.18 No.7, pp.713-723
Abstract
Despite advances in resolving the structures of multi-pass membrane proteins, little is known about the native folding pathways of these complex structures. Using single-molecule magnetic tweezers, we here report a folding pathway of purified human glucose transporter 3 (GLUT3) reconstituted within synthetic lipid bilayers. The N-terminal major facilitator superfamily (MFS) fold strictly forms first, serving as a structural template for its C-terminal counterpart. We found polar residues comprising the conduit for glucose molecules present major folding challenges. The endoplasmic reticulum membrane protein complex facilitates insertion of these hydrophilic transmembrane helices, thrusting GLUT3's microstate sampling toward folded structures. Final assembly between the N- and C-terminal MFS folds depends on specific lipids that ease desolvation of the lipid shells surrounding the domain interfaces. Sequence analysis suggests that this asymmetric folding propensity across the N- and C-terminal MFS folds prevails for metazoan sugar porters, revealing evolutionary conflicts between foldability and functionality faced by many multi-pass membrane proteins.
ISSN
1552-4450
URI
https://hdl.handle.net/10371/202525
DOI
https://doi.org/10.1038/s41589-022-01002-w
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  • College of Natural Sciences
  • School of Biological Sciences
Research Area Cryogenic Electron Microscopy (Cryo-EM), Structural Biology, 분자생물학, 생물물리학, 생화학

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