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Distinct protein interfaces in transmembrane domains suggest an in vivo folding model

¹ Cambridge Centre for Molecular Recognition, Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, United Kingdom
² The Alexander Silberman Institute of Life Sciences, Department of Biological Chemistry, The Hebrew University, Givat-Ram, Jerusalem, 91904, Israel

(RECEIVED March 7, 2004; FINAL REVISION July 15, 2004; ACCEPTED July 16, 2004)

Given the known high-resolution structures of -helical transmembrane domains, we show that there are statistically distinct classes of transmembrane interfaces which relate to the folding and oligomerization of transmembrane domains. Distinct types of interfaces have been categorized and refer to those between: the same polypeptide chain, different polypeptide chains, helices that are sequential neighbors, and those that are nonsequential. These different interfaces may reflect different phases in the mechanism of transmembrane domain folding and are consistent with the current experimental evidence pertaining to the folding and oligomerization of transmembrane domains. The classes of helix-helix interfaces have been identified in terms of the numbers and different types of pairwise amino acid interactions. The specific measures used are interaction entropy, the information content of interacting partners compared to a random set of contacts, the amino acid composition of the classes and the abundances of specific amino acid pairs in close contact. Knowledge of the clear differences in the types of helix-helix contacts helps with the derivation of knowledge-based constraints which until now have focused on only the interiors of transmembrane domains as compared to the exterior. Taken together, an in vivo model for membrane protein folding is presented, which is distinct from the familiar two-stage model. The model takes into account the different interfaces of membrane helices defined herein, and the available data regarding folding in the translocation channel.

Keywords: membrane protein; protein folding; transmembrane helices; translocon

Reprint requests to: Timothy J. Stevens, Cambridge Centre for Molecular Recognition, Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK; e-mail: tjs23{at}cam.ac.uk; fax: +44-1223-766-002; or Isaiah T. Arkin, The Alexander Silberman Institute of Life Sciences, Department of Biological Chemistry, The Hebrew University, Givat-Ram, Jerusalem, 91904, Israel; e-mail: arkin{at}cc.huji.ac.il; fax: +972-2-658-4329.

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