Open AccessEfficient integration of transmembrane domains depends on the folding properties of the upstream sequences
Author(s) -
Marco Janoschke,
Mirjam Zimmermann,
Anna Brunauer,
Raffael Humbel,
Tina Junne,
Martin Spiess
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2102675118
Subject(s) - translocon , transmembrane protein , transmembrane domain , folding (dsp implementation) , membrane protein , biophysics , chaperone (clinical) , protein folding , chemistry , biology , membrane , biochemistry , crystallography , receptor , medicine , pathology , electrical engineering , engineering
Significance The topology of membrane proteins is defined by the successive integration of α-helical transmembrane domains at the Sec61 translocon. For each polypeptide segment of ∼20 residues entering the translocon, their combined hydrophobicities were previously shown to define membrane integration. Here, we discovered that different sequences preceding a potential transmembrane domain substantially affect the hydrophobicity threshold. Sequences that are rapidly folding, intrinsically disordered, very short, or strongly binding chaperones allow efficient integration at low hydrophobicity. Folding deficient mutant domains and artificial sequences not binding chaperones interfered with membrane integration likely by remaining partially unfolded and exposing hydrophobic surfaces that compete with the translocon for the emerging transmembrane segment, reducing integration efficiency. Rapid folding or strong chaperone binding thus promote efficient integration.