Natural constraints, folding, motion, and structural stability in transmembrane helical proteins (original) (raw)

Structural Determinants of Transmembrane Helical Proteins

Structure, 2009

We identify a structural feature of transmembrane helical proteins that restricts their conformational space and suggests a new way of understanding the construction and stability of their native states. We show that five kinds of well-known specific favorable interhelical interactions (hydrogen bonds, aromatic interactions, salt bridges, and two interactions from packing motifs) precisely determine the packing of the transmembrane helices in 15 diverse proteins. To show this, we iteratively reassemble the helix bundle of each protein using only these interactions, generic interaction geometries, and individual helix backbone conformations. On average, the representative set of rebuilt structures best satisfying the constraints imposed by the five types of interhelical interactions has an average Ca root-mean-square deviation from the native of 1.03 Å . Implications for protein folding, structure and motion prediction, modeling, and design are discussed.

Deciphering the folding kinetics of transmembrane helical proteins

Proceedings of the National Academy of Sciences, 2000

Nearly a quarter of genomic sequences and almost half of all receptors that are likely to be targets for drug design are integral membrane proteins. Understanding the detailed mechanisms of the folding of membrane proteins is a largely unsolved, key problem in structural biology. Here, we introduce a general model and use computer simulations to study the equilibrium properties and the folding kinetics of a C ␣-based two-helix bundle fragment (comprised of 66 aa) of bacteriorhodopsin. Various intermediates are identified and their free energy are calculated together with the free energy barrier between them. In 40% of folding trajectories, the folding rate is considerably increased by the presence of nonobligatory intermediates acting as traps. In all cases, a substantial portion of the helices is rapidly formed. This initial stage is followed by a long period of consolidation of the helices accompanied by their correct packing within the membrane. Our results provide the framework for understanding the variety of folding pathways of helical transmembrane proteins.

Sequence motifs, polar interactions and conformational changes in helical membrane proteins

Current Opinion in Structural Biology, 2003

The a helices of transmembrane proteins interact to form higher order structures. These interactions are frequently mediated by packing motifs (such as GxxxG) and polar residues. Recent structural data have revealed that small sidechains are able to both stabilize helical membrane proteins and allow conformational changes in the structure. The strong interactions involving polar sidechains often contribute to protein misfolding or malfunction.

A sequence and structural study of transmembrane helices

Journal of computer-aided molecular design, 2001

A comparison is made between the distribution of residue preferences, three dimensional nearest neighbour contacts, preferred rotamers, helix-helix crossover angles and peptide bond angles in three sets of proteins: a non-redundant set of accurately determined globular protein structures, a set of four-helix bundle structures and a set of membrane protein structures. Residue preferences for the latter two sets may reflect overall helix stabilising propensities but may also highlight differences arising out of the contrasting nature of the solvent environments in these two cases. The results bear out the expectation that there may be differences between residue type preferences in membrane proteins and in water soluble globular proteins. For example, the beta-branched residue types valine and isoleucine are considerably more frequently encountered in membrane helices. Likewise, glycine and proline. residue types normally associated with 'helix-breaking' propensity are found t...

Large Tilts in Transmembrane Helices Can Be Induced during Tertiary Structure Formation

Journal of Molecular Biology, 2014

While early structural models of helix-bundle integral membrane proteins posited that the transmembrane α-helices [transmembrane helices (TMHs)] were orientated more or less perpendicular to the membrane plane, there is now ample evidence from high-resolution structures that many TMHs have significant tilt angles relative to the membrane. Here, we address the question whether the tilt is an intrinsic property of the TMH in question or if it is imparted on the TMH during folding of the protein. Using a glycosylation mapping technique, we show that four highly tilted helices found in multi-spanning membrane proteins all have much shorter membrane-embedded segments when inserted by themselves into the membrane than seen in the high-resolution structures. This suggests that tilting can be induced by tertiary packing interactions within the protein, subsequent to the initial membrane-insertion step.

Repositioning of transmembrane alpha-helices during membrane protein folding

Journal of molecular biology, 2010

We have determined the optimal placement of individual transmembrane helices in the Pyrococcus horikoshii GltPh glutamate transporter homolog in the membrane. The results are in close agreement with theoretical predictions based on hydrophobicity, but do not, in general, match the known three-dimensional structure, suggesting that transmembrane helices can be repositioned relative to the membrane during folding and oligomerization. Theoretical analysis of a database of membrane protein structures provides additional support for this idea. These observations raise new challenges for the structure prediction of membrane proteins and suggest that the classical two-stage model often used to describe membrane protein folding needs to be modified.

Helix packing in membrane proteins 1 1 Edited by G. von Heijne

Journal of Molecular Biology, 1997

A survey of 45 transmembrane (TM) helices and 88 helix packing interactions in three independent transmembrane protein structures reveals the following features. (1) Helix lengths range from 14 to 36 residues with an average length of 26.4 residues. There is a preference for lengths greater than 20 residues. (2) The helices are tilted with respect to the bilayer normal by an average of 21 , but there is a decided preference for smaller tilt angles. The distribution of helix packing angles is very different than for soluble proteins. The most common packing angles for TM helices are centered around 20 while for soluble proteins packing angles of around À35 are the most prevalent. (4) The average distance of closest approach is 9.6 A Ê , which is the same as soluble proteins. There is no preference for the positioning of the point of closest approach along the length of the helices. (6) It is almost a rule that TM helices pack against neighbors in the sequence. Of the 37 helices that have a sequence neighbor, 36 of them are in signi®cant contact with a neighbor. (7) An antiparallel orientation is more prevalent than a parallel orientation and antiparallel interactions are more intimate on average. The general features of helix bundle membrane protein architecture described in this survey should prove useful in the modeling of helix bundle transmembrane proteins.