Abstract
Monotopic membrane proteins integrate into the lipid bilayer via reentrant hydrophobic domains that enter and exit on a single face of the membrane. Whereas many membrane-spanning proteins have been structurally characterized and transmembrane topologies can be predicted computationally, relatively little is known about the determinants of membrane topology in monotopic proteins. Recently, we reported the X-ray structure determination of PglC, a full-length monotopic membrane protein with phosphoglycosyl transferase (PGT) activity. The definition of this unique structure has prompted in vivo, biochemical, and computational analyses to understand and define key motifs that contribute to the membrane topology and to provide insight into the dynamics of the enzyme in a lipid bilayer environment. Using the new information gained from studies on the PGT superfamily we demonstrate that two motifs exemplify principles of topology determination that can be applied to the identification of reentrant domains among diverse monotopic proteins of interest.
Highlights
Membrane proteins represent an essential and diverse component of the proteome
We demonstrate that the principles of reentrant membrane helix (RMH) formation identified in PglC are broadly generalizable by using them to identify a reentrant topology in LpxM, a fatty acid acyltransferase involved in the biosynthesis of lipid A
The crystal structure of PglC shows that the N-terminal hydrophobic domain forms a reentrant membrane helix (RMH) that anchors the fold in the membrane (Ray et al, 2018)
Summary
Membrane proteins represent an essential and diverse component of the proteome. Our understanding of how integral membrane proteins are folded and inserted into the membrane continues to evolve with the development of more sophisticated structural, biochemical, and computational tools. Current bioinformatics approaches (Elazar et al, 2016; Krogh et al, 2001; Tsirigos et al, 2015) enable a relatively reliable prediction of transmembrane helix topology in polytopic and bitopic membrane proteins on the basis of hydrophobicity, homology with known protein structures, and the ‘positiveinside rule’, by which membrane proteins have been empirically determined to preferentially adopt topologies that position positively charged residues at the cytoplasmic face of the membrane (Gafvelin and von Heijne, 1994; Heijne, 1986; von Heijne, 2006), among other parameters.
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