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标题：Efficient integration of transmembrane domains depends on the folding properties of the upstream sequences
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作者：Marco Janoschke ; Mirjam Zimmermann ; Anna Brunauer 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：33
DOI：10.1073/pnas.2102675118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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. The topology of most membrane proteins is defined by the successive integration of α-helical transmembrane domains at the Sec61 translocon. The translocon provides a pore for the transfer of polypeptide segments across the membrane while giving them lateral access to the lipid. For each polypeptide segment of ∼20 residues, the combined hydrophobicities of its constituent amino acids were previously shown to define the extent of membrane integration. Here, we discovered that different sequences preceding a potential transmembrane domain substantially affect its hydrophobicity requirement for integration. Rapidly folding domains, sequences that are intrinsically disordered or very short or capable of binding chaperones with high affinity, allow for efficient transmembrane integration with low-hydrophobicity thresholds for both orientations in the membrane. In contrast, long protein fragments, folding-deficient mutant domains, and artificial sequences not binding chaperones interfered with membrane integration, requiring higher hydrophobicity. We propose that the latter sequences, as they compact on their hydrophobic residues, partially folded but unable to reach a native state, expose hydrophobic surfaces that compete with the translocon for the emerging transmembrane segment, reducing integration efficiency. The results suggest that rapid folding or strong chaperone binding is required for efficient transmembrane integration.
关键词：enmembrane proteins;molecular chaperones;protein folding;Sec61 translocon;topogenesis