Abstract
-barrel membrane proteins play an important role in controlling the exchange and transport of ions and organic molecules across bacterial and mitochondrial outer membranes. They are also major regulators of apoptosis and are important determinants of bacterial virulence. In contrast to -helical membrane proteins, their evolutionary pattern of residue substitutions has not been quantified, and there are no scoring matrices appropriate for their detection through sequence alignment. Using a Bayesian Monte Carlo estimator, we have calculated the instantaneous substitution rates of transmembrane domains of bacterial -barrel membrane proteins. The scoring matrices constructed from the estimated rates, called bbTM for -barrel Transmembrane Matrices, improve significantly the sensitivity in detecting homologs of -barrel membrane proteins, while avoiding erroneous selection of both soluble proteins and other membrane proteins of similar composition. The estimated evolutionary patterns are general and can detect -barrel membrane proteins very remote from those used for substitution rate estimation. Furthermore, despite the separation of 2–3 billion years since the proto-mitochondrion entered the proto-eukaryotic cell, mitochondria outer membrane proteins in eukaryotes can also be detected accurately using these scoring matrices derived from bacteria. This is consistent with the suggestion that there is no eukaryote-specific signals for translocation. With these matrices, remote homologs of -barrel membrane proteins with known structures can be reliably detected at genome scale, allowing construction of high quality structural models of their transmembrane domains, at the rate of 131 structures per template protein. The scoring matrices will be useful for identification, classification, and functional inference of membrane proteins from genome and metagenome sequencing projects. The estimated substitution pattern will also help to identify key elements important for the structural and functional integrity of -barrel membrane proteins, and will aid in the design of mutagenesis studies.
Highlights
As one of the two classes of integral membrane proteins, bbarrel membrane proteins are found in the outer membranes of gram negative bacteria, mitochondria, and chloroplasts
As bacterial porins enable the diffusion of hydrophilic antibiotics through outer membranes, mutation of their barrel interior is the basis of a common mechanism of bacterial drug resistance [12,13]. b-barrel membrane proteins are excellent targets for developing new antibacterial drugs
We followed the procedure of Jackups et al [23] and select the fragments embedded within the outer membrane region
Summary
As one of the two classes of integral membrane proteins, bbarrel membrane proteins are found in the outer membranes of gram negative bacteria, mitochondria, and chloroplasts Because they are located in the first barrier of bacteria and are in contact with the extracellular environment, they are often key factors providing control of the diffusion, exchange, and transport of ions and organic molecules [1,2,3,4,5]. They are involved in the transmission of signals in response to stimuli and, as enzymes, in the maintaining of the stability of the outer membrane [2,6]. A promising example is the recent discovery of a new peptidomimetic antibiotic that perturbs the critical LPS transport function of the b-barrel membrane protein LptD [11]
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