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J. Adv. Res., Volume 87, September 2026, Pages 149-162 | https://doi.org/10.1016/j.jare.2025.11.066 Unique molecular architecture of N-glycosylated TM4SF5 dimer highlights evolutionary and structural divergence among small four-transmembrane protein families

Yoonji Lee ^a,1, Ji Eon Kim ^b,1,2, Wonsik Kim ^b, Soyeon Kim ^b, Ri Han ^a, Donghyuk Suh^c, Eunmi Kim ^b, Eun-Ae Shin^b, Kyung-hee Pyo ^b, Jae-Ho Lee ^b, Sanghee Yoon^c, Yong-In Kim ^d, Je-Yoel Cho^d, Sun Choi ^c, Jung Weon Lee ^b

^aCollege of Pharmacy, Chung-Ang University, Seoul 06974, the Republic of Korea
^bDepartment of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, the Republic of Korea
^cGlobal AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, the Republic of Korea
^dDepartment of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul 08826, the Republic of Korea

¹These authors contributed equally to this work.
²Current address: Department of Integrative Bioscience & Biotechnology, Sejong University, Seoul 05006, Republic of Korea.

Abstract

Introduction
Membrane proteins, including small four-transmembrane proteins, play roles in membrane organization and signal transduction. Generally, they share capacities for protein–protein association and subcellular translocation to regulate cellular functions.

Objectives
Despite known commonalities and differences in structure and function, the relationships among the tetraspanin, CD20-like, golgi 4-transmembrane spanning transporter (Mtp), and transmembrane 4 L six (L6) families remain unclear.

Methods
Here, we mostly compared TM4SF5, a transmembrane 4 L6 family member, to the genuine tetraspanins and the CD20-like family, exploring unique aspects that evolved from the small four-transmembrane proteins.

Results
TM4SF5 and other L6 membrane proteins have two conserved cysteines, affecting N-glycosylation in the large extracellular loop (LEL) and favoring a dimeric state, whereas the tetraspanins maintained their cysteine residues in addition to the CCG motif. However, TM4SF5 and other L6 membrane proteins have more sequence similarity to proteins in the CD20-like family, which lack these features in the LEL. Uniquely, TM4SF5 and other L6 membrane proteins have a β-sheet configuration in the LEL, unlike other small four-transmembrane proteins with α-helices.

Conclusion
Therefore, the unique features in the LEL and the N-glycosylation of TM4SF5 may contribute to dimer formation and cholesterol binding, potentially influencing regulatory roles in liver malignancy development.

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