Helical membrane protein conformations and their environment (original) (raw)
Related papers
Influences of membrane mimetic environments on membrane protein structures
Annual review of biophysics, 2013
The number of membrane protein structures in the Protein Data Bank is becoming significant and growing. Here, the transmembrane domain structures of the helical membrane proteins are evaluated to assess the influences of the membrane mimetic environments. Toward this goal, many of the biophysical properties of membranes are discussed and contrasted with those of the membrane mimetics commonly used for structure determination. Although the mimetic environments can perturb the protein structures to an extent that potentially gives rise to misinterpretation of functional mechanisms, there are also many structures that have a native-like appearance. From this assessment, an initial set of guidelines is proposed for distinguishing native-like from nonnative-like membrane protein structures. With experimental techniques for validation and computational methods for refinement and quality assessment and enhancement, there are good prospects for achieving native-like structures for these ver...
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.
Molecular Packing and Packing Defects in Helical Membrane Proteins
Biophysical Journal, 2005
The packing of helices spanning lipid bilayers is crucial for the stability and function of a-helical membrane proteins. Using a modified Voronoi procedure, we calculated packing densities for helix-helix contacts in membrane spanning domains. Our results show that the transmembrane helices of protein channels and transporters are significantly more loosely packed compared with helices in globular proteins. The observed packing deficiencies of these membrane proteins are also reflected by a higher amount of cavities at functionally important sites. The cavities positioned along the gated pores of membrane channels and transporters are noticeably lined by polar amino acids that should be exposed to the aqueous medium when the protein is in the open state. In contrast, nonpolar amino acids surround the cavities in those protein regions where large rearrangements are supposed to take place, as near the hinge regions of transporters or at restriction sites of protein channels. We presume that the observed deficiencies of helix-helix packing are essential for the helical mobility that sustains the function of many membrane protein channels and transporters.
How Membranes Shape Protein Structure
Journal of Biological Chemistry, 2001
Constitutive ␣-helical membrane proteins (MPs) 1 are assembled in membranes by means of a translocation/insertion process that involves the translocon complex (1). After release into the membrane's bilayer fabric, a MP resides stably in a thermodynamic free energy minimum (evidence reviewed in Refs. 2 and 3). This means that the prediction of MP structure from the amino acid sequence is fundamentally a problem of physical chemistry, albeit a complex one. Physical influences that shape MP structure include interactions of the polypeptide chains with water, each other, the bilayer hydrocarbon core, the bilayer interfaces, and cofactors . Two recent reviews (3, 4) provide extensive discussions of the evolution, structure, and thermodynamic stability of MPs. Here we provide a distilled (and updated) overview that addresses four broad questions.
Structural adaptations of proteins to different biological membranes
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013
To gain insight into adaptations of proteins to their membranes, intrinsic hydrophobic thicknesses, distributions of different chemical groups and profiles of hydrogen-bonding capacities (α and β) and the dipolarity/ polarizability parameter (π*) were calculated for lipid-facing surfaces of 460 integral α-helical, β-barrel and peripheral proteins from eight types of biomembranes. For comparison, polarity profiles were also calculated for ten artificial lipid bilayers that have been previously studied by neutron and X-ray scattering. Estimated hydrophobic thicknesses are 30-31 Å for proteins from endoplasmic reticulum, thylakoid, and various bacterial plasma membranes, but differ for proteins from outer bacterial, inner mitochondrial and eukaryotic plasma membranes (23.9, 28.6 and 33.5 Å, respectively). Protein and lipid polarity parameters abruptly change in the lipid carbonyl zone that matches the calculated hydrophobic boundaries. Maxima of positively charged protein groups correspond to the location of lipid phosphates at 20-22 Å distances from the membrane center. Locations of Tyr atoms coincide with hydrophobic boundaries, while distributions maxima of Trp rings are shifted by 3-4 Å toward the membrane center. Distributions of Trp atoms indicate the presence of two 5-8 Å-wide midpolar regions with intermediate π* values within the hydrocarbon core, whose size and symmetry depend on the lipid composition of membrane leaflets. Midpolar regions are especially asymmetric in outer bacterial membranes and cell membranes of mesophilic but not hyperthermophilic archaebacteria, indicating the larger width of the central nonpolar region in the later case. In artificial lipid bilayers, midpolar regions are observed up to the level of acyl chain double bonds.
Biochemistry, 2012
Among the growing number of membrane protein structures in the Protein Data Bank, there are many transmembrane domains that appear to be native-like; at the same time there are others that appear to have less than complete native-like character. Hence there is an increasing need for validation tools that distinguish native-like from nonnative-like structures. Membrane mimetics used in protein structural characterizations differ in numerous physicochemical properties from native membranes and provide many opportunities for introducing nonnative-like features into membrane protein structures. One possible approach for validating membrane protein structures is based on the use of glycine residues in transmembrane domains. Here, we have reviewed the membrane protein structure database and identified a set of benchmark proteins that appear to be native like. In these structures, conserved glycine residues rarely face the lipid interstices, and many of them participate in close helix-helix packing. Glycine-based validation allowed the identification of nonnative-like features in several membrane proteins and also shows the potential for verifying the native-like character for numerous other membrane protein structures. Alpha-helical membrane protein structures can be influenced by the membrane mimetic environments in subtle and not so subtle ways (1-6). Anfinsen in 1973 (7) stated "that the native conformation (of a protein) is determined by the totality of interatomic interactions and hence by the amino acid sequence in a given environment." Therefore, the interactions from the heterogeneous membrane environment contribute to the sum of interactions responsible for defining the three-dimensional structure of a membrane protein. Here, we focus on the influence of the physical properties of membrane environments instead of the influence of specific lipids. Recently, a detailed description of how promiscuous membrane proteins can be in their interactions with different lipids has been published (8). A challenge for membrane protein structural biologists is to mimic the membrane environment adequately to stabilize the native protein structure, while preparing a sample that is appropriate for the specific structural technique. Only bacteriorhodopsin has been characterized in its native membrane environment (9). A few others have been characterized in liquid crystalline lipid bilayers (4, 10-14) and more in the presence of lipids.(15-17) The
Empirical lipid propensities of amino acid residues in multispan alpha helical membrane proteins
Proteins: Structure, Function, and Bioinformatics, 2005
Characterizing the interactions between amino acid residues and lipid molecules is important for understanding the assembly of transmembrane helices and for studying membrane protein folding. In this study we develop TMLIP (Trans-Membrane helix-LIPid), an empirically derived propensity of individual residue types to face lipid membrane based on statistical analysis of highresolution structures of membrane proteins. Lipid accessibilities of amino acid residues within the transmembrane (TM) region of 29 structures of helical membrane proteins are studied with a spherical probe of radius of 1.9 Å. Our results show that there are characteristic preferences for residues to face the headgroup region and the hydrocarbon core region of lipid membrane. Amino acid residues Lys, Arg, Trp, Phe, and Leu are often found exposed at the headgroup regions of the membrane, where they have high propensity to face phospholipid headgroups and glycerol backbones. In the hydrocarbon core region, the strongest preference for interacting with lipids is observed for Ile, Leu, Phe and Val. Small and polar amino acid residues are usually buried inside helical bundles and are strongly lipophobic. There is a strong correlation between various hydrophobicity scales and the propensity of a given residue to face the lipids in the hydrocarbon region of the bilayer. Our data suggest a possibly significant contribution of the lipophobic effect to the folding of membrane proteins. This study shows that membrane proteins have exceedingly apolar exteriors rather than highly polar interiors. Prediction of lipid-facing surfaces of boundary helices using TMLIP1 results in a 54% accuracy, which is significantly better than random (25% accuracy). We also compare performance of TMLIP with another lipid propensity scale, kPROT, and with several hydrophobicity scales using hydrophobic moment analysis. Proteins 2005;59:496 -509.
Progress in structure prediction of α-helical membrane proteins
Current Opinion in Structural Biology, 2006
Transmembrane (TM) proteins comprise 20-30% of the genome but, because of experimental difficulties, they represent less than 1% of the Protein Data Bank. The dearth of membrane protein structures makes computational prediction a potentially important means of obtaining novel structures. Recent advances in computational methods have been combined with experimental data to constrain the modeling of three-dimensional structures. Furthermore, threading and ab initio modeling approaches that were effective for soluble proteins have been applied to TM domains. Surprisingly, experimental structures, proteomic analyses and bioinformatics have revealed unexpected architectures that counter long-held views on TM protein structure and stability. Future computational and experimental studies aimed at understanding the thermodynamic and evolutionary bases of these architectural details will greatly enhance predictive capabilities.
Progress in structure prediction of alpha-helical membrane proteins
Current opinion in structural biology, 2006
Transmembrane (TM) proteins comprise 20-30% of the genome but, because of experimental difficulties, they represent less than 1% of the Protein Data Bank. The dearth of membrane protein structures makes computational prediction a potentially important means of obtaining novel structures. Recent advances in computational methods have been combined with experimental data to constrain the modeling of three-dimensional structures. Furthermore, threading and ab initio modeling approaches that were effective for soluble proteins have been applied to TM domains. Surprisingly, experimental structures, proteomic analyses and bioinformatics have revealed unexpected architectures that counter long-held views on TM protein structure and stability. Future computational and experimental studies aimed at understanding the thermodynamic and evolutionary bases of these architectural details will greatly enhance predictive capabilities.