TY - JOUR
T1 - Evolutionary balance between foldability and functionality of a glucose transporter
AU - Choi, Hyun-Kyu
AU - Kang, Hyunook
AU - Lee, Chanwoo
AU - Kim, Hyun gyu
AU - Phillips, Ben p.
AU - Park, Soohyung
AU - Tumescheit, Charlotte
AU - Kim, Sang ah
AU - Lee, Hansol
AU - Roh, Soung-Hun
AU - Hong, Heedeok
AU - Steinegger, Martin
AU - Im, Wonpil
AU - Miller, Elizabeth a.
AU - Choi, Hee-Jung
AU - Yoon, Tae-Young
N1 - © The Author(s), under exclusive licence to Springer Nature America, Inc. 2022
PY - 2022/7/1
Y1 - 2022/7/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85128986784&origin=inward
U2 - 10.1038/s41589-022-01002-w
DO - 10.1038/s41589-022-01002-w
M3 - Article
C2 - 35484435
SN - 1552-4450
VL - 18
SP - 713
EP - 723
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 7
ER -