Although the structures of many -barrel membrane proteins are available, our knowledge of the principles that govern their energetics and oligomerization states is incomplete. Here we describe a computational method to study the transmembrane (TM) domains of -barrel membrane proteins. Our method is based on a physical interaction model, a simplified conformational space for efficient enumeration, and an empirical potential function from a detailed combinatorial analysis. Using this method, we can identify weakly stable regions in the TM domain, which are found to be important structural determinants for -barrel membrane proteins. By calculating the melting temperatures of the TM strands, our method can also assess the stability of -barrel membrane proteins. Predictions on membrane enzyme PagP are consistent with recent experimental NMR and mutant studies. We have also discovered that out-clamps, in-plugs, and oligomerization are 3 general mechanisms for stabilizing weakly stable TM regions. In addition, we have found that extended and contiguous weakly stable regions often signal the existence of an oligomer and that strands located in the interfaces of protein-protein interactions are considerably less stable. Based on these observations, we can predict oligomerization states and can identify the interfaces of protein-protein interactions for -barrel membrane proteins by using either structure or sequence information. In a set of 25 nonhomologous proteins with known structures, our method successfully predicted whether a protein forms a monomer or an oligomer with 91% accuracy; in addition, our method identified with 82% accuracy the protein-protein interaction interfaces by using sequence information only when correct strands are given.in-plug ͉ membrane protein oligomerization ͉ out-clamp ͉ protein-protein interaction ͉ weakly stable TM strand D eveloping a general understanding of how proteins behave in membranes is of fundamental importance. -barrel membrane proteins, one of the 2 major structural classes of membrane proteins, have been studied extensively. Currently, structures of 70 -barrel membrane proteins have been resolved, and much has been learned about their thermodynamic stability (1), folding kinetics (2-4), biogenesis (5), and biological functions (6). These membrane proteins are thought to have very regular structures, with the basic principles of their architectural organization well understood (7). An overwhelming structural feature is the existence of an extensive regular hydrogen bond network between the transmembrane (TM) -strands, which is thought to confer extreme stability on the proteins (8).However, -barrel membrane proteins have diverse structures and often deviate significantly from the standard barrel architecture. For example, there are often small ␣-helices and -strands, called in-plugs, found inside the -barrel (9). Nonbarrel-embedded helices are also found to pack against the TM -strands (10). In addition, some -barrel membrane proteins exist in monomeric form, whe...
HighlightsSystemic inflammation impairs blood-brain barrier (BBB) in preclinical models.In humans, BBB function was assessed by the CSF/serum albumin ratio (CSAR).Systemic inflammation did not affect CSAR in the non-inflamed brain.Systemic inflammation increased CSAR in the presence of brain inflammation.The diseased BBB has an increased susceptibility to systemic inflammation.
Background: VDAC1 was shown to undergo oligomeric assembly, an event that is coupled to apoptosis induction. Results: Structure-and computation-based predications of VDAC1 oligomerization sites were confirmed. Conclusion: Upon apoptosis induction, VDAC1 undergoes conformational changes and oligomerization. Significance: Dissection of VDAC1 dimerization/oligomerization provides structural insight into the oligomeric status of cellular VDAC1 under physiological and apoptotic conditions.
Membrane proteins function in the diverse environment of the lipid bilayer. Experimental evidence suggests that some lipid molecules bind tightly to specific sites on the membrane protein surface. These lipid molecules often act as co-factors and play important functional roles. In this study, we have assessed the evolutionary selection pressure experienced at lipid-binding sites in a set of α-helical and β-barrel membrane proteins using posterior probability analysis of the ratio of synonymous vs. nonsynonymous substitutions (ω-ratio). We have also carried out a geometric analysis of the membrane protein structures to identify residues in close contact with co-crystallized lipids. We found that residues forming cholesterol-binding sites in both β2-adrenergic receptor and Na+-K+-ATPase exhibit strong conservation, which can be characterized by an expanded cholesterol consensus motif for GPCRs. Our results suggest the functional importance of aromatic stacking interactions and interhelical hydrogen bonds in facilitating protein-cholesterol interactions, which is now reflected in the expanded motif. We also find that residues forming the cardiolipin-binding site in formate dehydrogenase-N γ-subunit and the phosphatidylglycerol binding site in KcsA are under strong purifying selection pressure. Although the lipopolysaccharide (LPS)-binding site in ferric hydroxamate uptake receptor (FhuA) is only weakly conserved, we show using a statistical mechanical model that LPS binds to the least stable FhuA β-strand and protects it from the bulk lipid. Our results suggest that specific lipid binding may be a general mechanism employed by β-barrel membrane proteins to stabilize weakly stable regions. Overall, we find that the residues forming specific lipid binding sites on the surfaces of membrane proteins often experience strong purifying selection pressure.
Regulation of cell growth and cell division has a fundamental role in tissue formation, organ development, and cancer progression. Remarkable similarities in the topological distributions were found in a variety of proliferating epithelia in both animals and plants. At the same time, there are species with significantly varied frequency of hexagonal cells. Moreover, local topology has been shown to be disturbed on the boundary between proliferating and quiescent cells, where cells have fewer sides than natural proliferating epithelia. The mechanisms of regulating these topological changes remain poorly understood. In this study, we use a mechanical model to examine the effects of orientation of division plane, differential proliferation, and mechanical forces on animal epithelial cells. We find that regardless of orientation of division plane, our model can reproduce the commonly observed topological distributions of cells in natural proliferating animal epithelia with the consideration of cell rearrangements. In addition, with different schemes of division plane, we are able to generate different frequency of hexagonal cells, which is consistent with experimental observations. In proliferating cells interfacing quiescent cells, our results show that differential proliferation alone is insufficient to reproduce the local changes in cell topology. Rather, increased tension on the boundary, in conjunction with differential proliferation, can reproduce the observed topological changes. We conclude that both division plane orientation and mechanical forces play important roles in cell topology in animal proliferating epithelia. Moreover, cell memory is also essential for generating specific topological distributions.
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