14transmembranehelix

14-transmembrane-helix proteins, abbreviated as 14-TMH, are membrane proteins in which the polypeptide chain traverses the lipid bilayer fourteen times, giving rise to fourteen alpha-helical segments that span the membrane. The architecture yields a compact, multi-pass topology that can orient both termini on the same side or on opposite sides depending on the protein, and it often forms a central scaffold for substrate translocation or signaling.

Such topologies are less common than the many GPCRs with seven helices or transporters with 12 helices. They are typically associated with transporter families or channels that rely on many cooperating helices to create binding pockets or gating networks. The precise arrangement of the 14 helices is usually determined by a combination of sequence hydrophobicity, helix-helix packing, and evolutionary duplication events that generate mirror-symmetric repeats.

Identification and characterization rely on computational predictions and experimental validation. Hydrophobicity plots and topology prediction algorithms can suggest fourteen transmembrane segments, but experimental approaches such as cysteine-scanning mutagenesis, protease protection assays, and increasingly, X-ray crystallography or cryo-electron microscopy provide confirmation. In annotations and databases, 14-TMH is often used as a descriptive label rather than a strict functional category, with individual members assigned to larger families based on conserved sequences and structural features. Understanding 14-TMH proteins contributes to insights into membrane transport mechanisms and the evolution of complex membrane architectures.