Evolutionary balance between foldability and functionality of a glucose transporter

Hyun-Kyu Choi, Hyunook Kang, Chanwoo Lee, Hyun gyu Kim, Ben p. Phillips, Soohyung Park, Charlotte Tumescheit, Sang ah Kim, Hansol Lee, Soung-Hun Roh, Heedeok Hong, Martin Steinegger, Wonpil Im, Elizabeth a. Miller (Lead / Corresponding author), Hee-Jung Choi (Lead / Corresponding author), Tae-Young Yoon (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)713-723
Number of pages27
JournalNature Chemical Biology
Issue number7
Early online date28 Apr 2022
Publication statusPublished - 1 Jul 2022


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