![]() ![]() (a−f) Enriched sequence motifs create unique trimer-specific interatomic van der Waals (black dotted line) and hydrogen bonding (red dotted line) interactions in local regions of the trimers defined by red and blue planes at the center of each panel. ![]() The reported motifs were found in at least 20% of trimer interacting regions in a given class and are ordered from left to right according to their frequency of occurrence in that class. Each helix is colored using a blue to red spectrum from N to Cterminus. The topology and helix number of the reference trimer for each class are described in Supplementary Table 1. For example, if a motif is found on helices 1 and 2 in a given trimer, the corresponding helix numbers are given as: ½. The helix number describes on which helix or helices of a reference trimer are found the motifs. Residues in the motif are aligned along an ideal helix following their sequence separation (register). Sequence motifs are constituted by pairs of amino acids belonging to three chemical classes (G/A/S, small: glycine, alanine or serine I/L/V/M, large: isoleucine, leucine, valine or methionine F/W/Y or aromatic: phenylalanine, tryptophan or tyrosine). (a−f) Descriptions of six largest classes of TMH trimer structure with specific sequence motifs enriched at the interhelical interface. Our results reveal universal sequence-structure principles governing the complex anatomy and plasticity of multipass membrane proteins that may guide de novo structure prediction, design, and studies of folding and dynamics. Interacting TMHs' topology and local protein conformational flexibility were remarkably well predicted in a blinded fashion from the identified binding-hotspot motifs. Each class is enriched in recurrent sequence motifs from functionally unrelated proteins, revealing unforeseen consensus and evolutionary conserved networks of stabilizing interhelical contacts. We found that membrane proteins can be deconstructed in interacting TMH trimer units, which mostly fold into six distinct structural classes of topologies and conformations. Here we describe a comprehensive analysis of the sequence-structure relationships at multiple interacting TMHs from all membrane proteins with structures in the Protein Data Bank (PDB). How transmembrane helix (TMH) sequences encode the topology and conformational flexibility regulating these functions remains poorly understood. Multipass membrane proteins perform critical signal transduction and transport across membranes. ![]()
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