Monotopic Membrane Proteins Join the Fold

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2019-01, Vol.44 (1), p.7-20
• Main Authors: Allen, Karen N., Entova, Sonya, Ray, Leah C., Imperiali, Barbara
• Format: Article
• Language: English
• Subjects: Animals; Databases, Protein; Humans; Hydrophobic and Hydrophilic Interactions; membrane interface; Membrane Proteins - chemistry; membrane–protein interaction; membranome; monotopic enzymes
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2018.09.013

Monotopic membrane proteins, classified by topology, are proteins that embed into a single face of the membrane. These proteins are generally underrepresented in the Protein Data Bank (PDB), but the past decade of research has revealed new examples that allow the description of generalizable features. This Opinion article summarizes shared characteristics including oligomerization states, modes of membrane association, mechanisms of interaction with hydrophobic or amphiphilic substrates, and homology to soluble folds. We also discuss how associations of monotopic enzymes in pathways can be used to promote substrate specificity and product composition. These examples highlight the challenges in structure determination specific to this class of proteins, but also the promise of new understanding from future study of these proteins that reside at the interface. Monotopic proteins are underrepresented in the PDB, with only 25 nonredundant structures currently constituting ∼0.06% of known structures. Many monotopic membrane proteins are homologous to soluble counterparts and use common structural features to embed shallowly in the membrane. Selected monotopic proteins engage more deeply in the membrane (e.g., associating via reentrant-helical domains). Monotopic enzymes are purposed for catalysis of reactions involving hydrophobic or amphiphilic substrates not readily soluble in water. The active sites of monotopic enzymes may be at the membrane surface or distal to it, and the requirement for hydrophobic substrate extraction is dictated by the substrate and the relative orientations of the active site and the membrane. Association of multiple monotopic enzymes in pathways can be advantageously applied in the assembly of complex glycoconjugates.