Monotopic Membrane Proteins Join the Fold

Abstract

Monotopic membrane proteins, classified by topology, are proteins which embed into a single face of the membrane. These proteins are generally underrepresented in the protein data bank, but the last decade of research has revealed new examples that allow description of generalizable features. This review summarizes shared characteristics including oligomerization states, modes of membrane association, mechanisms of interactions with hydrophobic or amphiphilic substrates and homology to soluble folds. We also discuss how association of monotopic enzymes into 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.

Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs

“…The dimerization observed in the crystal structure is not uncommon to membrane proteins and is now attributed to mammalian FMOs. 58,68 Specifically, the oligomerization state aids membrane insertion as the protein occupies a larger membrane-surface area. 68 The inserted residues together form a large monotopic binding feature, which constitutively holds the enzyme in the With the AncFMOs all accommodating very similar active sites, substrate profiles are likely differentiated by the tunnels penetrating the scaffold.…”

A pilin chaperone required for the expression of electrically conductive Geobacter sulfurreducens pili

“…1D). Considering that no transmembrane domain was predicted from the Spc protein sequences, the Spc probably is a monotopic protein (Allen et al, 2019).…”

Structure and assembly of CAV1 8S complexes revealed by single particle electron microscopy

“…Unlike traditional transmembrane proteins, monotopic membrane proteins contain structural elements that enter and exit on a single face of the membrane as opposed to completely spanning the membrane bilayer. These proteins have been particularly recalcitrant for structural studies, as there are only a few with available structures (10,34,35). The vast majority of the monotopic membrane proteins with known structures are enzymes that share homology with soluble proteins that catalyze similar reactions.…”

“…These monotopic enzymes are typically assembled as either monomers or dimers (10). One exception is seipin, a dodecameric structural protein involved in biogenesis of lipid droplets (10,35). The caveolin family members Cav1 and Cav3 thus constitute additional examples of structural monotopic proteins that function as higher-ordered oligomers.…”

“…It has also been predicted to potentially contain a beta strand in the extreme C-terminal region (8). The 33-residue intramembrane domain forms an unusual reentrant helix-break-helix structure (9), defining caveolin as a member of the poorly understood class of monotopic membrane proteins (10). This hairpin-like domain inserts into the cytoplasmic face of the plasma membrane, placing both the N-and C-terminus in the cytoplasm.…”