The effect of loops on the structural organization of alpha-helical membrane proteins.
Loops connecting the transmembrane (TM) alpha-helices in membrane proteins are expected to affect the structural organization of the thereby connected helices and the helical bundles as a whole. This effect, which has been largely ignored previously, is studied here by analyzing the x-ray structures of 41 alpha-helical membrane proteins. First we define the loop flexibility ratio, R, and find that 53% of the loops are stretched, where a stretched loop constrains the distance between the two connected helices. The significance of this constraining effect is supported by experiments carried out with bacteriorhodopsin and rhodopsin, in which cutting or eliminating their (predominately stretched) loops has led to a decrease in protein stability, and for rhodopsin, in most cases, also to the destruction of the structure. We show that for nonstretched loops in the extramembranous regions, the fraction of hydrophobic residues is comparable to that for soluble proteins; furthermore (as is also the case for soluble proteins), the hydrophobic residues in these regions are preferentially buried. This is expected to lead to the compact structural organization of the loops, which is transferred to the TM helices, causing them to assemble. We argue that a soluble protein complexed with a membrane protein similarly promotes compactness; other properties of such complexes are also studied. We calculate complementary attractive interactions between helices, including hydrogen bonds and van der Waals interactions of sequential motifs, such as GXXXG. The relative and combined effects of all these factors on the association of the TM helices are discussed and protein structures with only a few of these factors are analyzed. Our study emphasizes the need for classifying membrane proteins into groups according to structural organization. This classification should be considered when procedures for structural analysis or prediction are developed and applied. Detailed analysis of each structure is provided at http://flan.blm.cs.cmu.edu/memloop/
Tastan
Oznur
O
Language Technologies Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
Klein-Seetharaman
Judith
J
Meirovitch
Hagai
H
D001436:Bacteriorhodopsins / Q000737:chemistry; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D012243:Rhodopsin / Q000737:chemistry
D008565:Membrane Proteins; D001436:Bacteriorhodopsins; D012243:Rhodopsin