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Peripheral Membrane Proteins: Promising Therapeutic Targets Across Domains of Life

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Peripheral Membrane Proteins: Promising Therapeutic Targets Across Domains of Life membranes Review Peripheral Membrane Proteins: Promising Therapeutic Targets across Domains of Life Deborah M. Boes 1, Albert Godoy-Hernandez 1 and Duncan G. G. McMillan 1,2,* 1 Department of Biotechnology, Delft University of Technology, Van der Maasweg 9, NL-2629 HZ Delft, The Netherlands; [email protected] (D.M.B.); [email protected] (A.G.-H.) 2 School of Fundamental Sciences, Massey University, Palmerston North, Private Bag 11 222, New Zealand * Correspondence: [email protected] Abstract: Membrane proteins can be classified into two main categories—integral and peripheral membrane proteins—depending on the nature of their membrane interaction. Peripheral membrane proteins are highly unique amphipathic proteins that interact with the membrane indirectly, using electrostatic or hydrophobic interactions, or directly, using hydrophobic tails or GPI-anchors. The nature of this interaction not only influences the location of the protein in the cell, but also the function. In addition to their unique relationship with the cell membrane, peripheral membrane proteins often play a key role in the development of human diseases such as African sleeping sickness, cancer, and atherosclerosis. This review will discuss the membrane interaction and role of periplasmic nitrate reductase, CymA, cytochrome c, alkaline phosphatase, ecto-5’-nucleotidase, acetylcholinesterase, alternative oxidase, type-II NADH dehydrogenase, and dihydroorotate dehydrogenase in certain diseases. The study of these proteins will give new insights into their function and structure, and may ultimately lead to ground-breaking advances in the treatment of severe diseases. Citation: Boes, D.M.; Godoy- Hernandez, A.; McMillan, D.G.G. Keywords: peripheral membrane proteins; human diseases; GPI-anchored proteins; electrostatic Peripheral Membrane Proteins: interactions; hydrophobic membrane anchor; drug targets Promising Therapeutic Targets across Domains of Life. Membranes 2021, 11, 346. https://doi.org/10.3390/ membranes11050346 1. Introduction The lipid membrane surrounding cells and their compartments hosts proteins that Academic Editor: Shiro Suetsugu perform functions essential for both cell physiology and disease progression. They are, by definition, located at the interface between two different environments, such as between the Received: 6 April 2021 cytoplasm and the extracellular space, or between the mitochondrial matrix and the inter- Accepted: 5 May 2021 membrane space [1]. Membrane proteins constitute about a third of all human proteins and Published: 8 May 2021 are categorized into two broad categories depending on their location [2]: integral mem- brane proteins (IMPs or ‘intrinsic proteins’) and peripheral membrane proteins (PMPs). Publisher’s Note: MDPI stays neutral IMPs are embedded in the phospholipid bilayer (Figure1) and contain one or more with regard to jurisdictional claims in published maps and institutional affil- membrane-spanning domains (transmembrane proteins). An associated class of proteins iations. are monotopic membrane proteins (MMPs; Figure1)[ 3], which functionally interact with the environment on one side of the membrane and are akin to a lipid-anchored PMP. We class them as a subsection of ‘peripheral membrane proteins’ in the context of this review. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Membranes 2021, 11, 346. https://doi.org/10.3390/membranes11050346 https://www.mdpi.com/journal/membranes Membranes 2021, 11, x FOR PEER REVIEW 2 of 22 Membranes 2021, 11, 346 2 of 21 FigureFigure 1. 1. Different types types of membrane of membrane proteins proteins shown in theshow celln membrane. in the cell Integral membrane. membrane Integral proteins aremembrane shown to span the entire membrane (Escherichia coli ATP synthase as example). Peripheral membrane proteins can be categorized into proteins are shown to span the entire membrane (Escherichia coli ATP synthase as example). Pe- two subtypes: proteins that only associate with the membrane via electrostatic or hydrophobic interactions (Caldalkalibacillus ripheralthermarum membranetype-II NADH proteins dehydrogenase can be ascategorized example), and into proteins two that subtypes: anchor themselves proteins in that the lipidonly bilayer associate using awith thehydrophobic membrane segment via electrostatic that does not spanor hydrophobic the entire membrane interactions (Desulfovibrio (Caldalkalibacillus vulgaris NrfH as example). thermarum 3D structuraltype-II NADHcartoons dehydrogenase of E. coli ATP synthase as ex (PDB:5T4Q)ample), [and4], D. proteins vulgaris NrfH that (PDB:2J7A) anchor [5th], emselvesShewanella frigidimarina in the lipidflavocytochrome bilayer using a hydrophobicc3 (PDB:1Y0P) [6 segment], and C. thermarum that doesNDH-2 not span (PDB:6BDO) the entire [7] were membrane rendered with (Desulfovibrio PyMol and the vulgaris figure compiledNrfH as in example).BioRender.com 3D [structural8]. cartoons of E. coli ATP synthase (PDB:5T4Q) [4], D. vulgaris NrfH (PDB:2J7A) [5], Shewanella frigidimarinaPMPs are a diverse flavocytochrome group including c3 (PDB:1Y0P) proteins that [6], associate and C. directly thermarum with the lipid NDH-2 (PDB:6BDO) [7]membrane were rendered and face with one PyMol side of a and lipid the membrane figure compiled (a true peripheral in BioRender.com membrane protein; [8]. PMP, Figure1) or indirectly via interactions with integral membrane proteins (a membrane- associated protein; MAP, Figure1). The core focus of this review are PMPs, although MAPs PMPs are a diversedirectly group associate including with the aforementioned proteins that monotopic associate membrane directly proteins, with referred the lipid to as membrane and face onesubset side of PMPs of a in lipid the context membra of thisne review. (a true PMPs peripheral associate with membrane the membrane protein; using a PMP, Figure 1) or indirectlyvariety of differentvia interactions mechanisms. with They integral can ‘nestle’ membrane into the membrane, proteins interacting (a mem- via a hydrophobic patch with the membrane interior, or only associate via interactions with the brane-associated protein;polar headMAP, groups Figure of the phospholipids1). The core [9 ].focus Two subsets of this of peripheralreview are membrane PMPs, proteins alt- hough MAPs directlywhich associate we particularly with the emphasize aforementioned in this review monotopic are lipid-anchored membrane proteins, proteins, which are referred to as subsetanchored of PMPs to the in lipid the bilayer cont byext a specialof this functionalized review. PMPs lipid embedded associate in the with membrane, the membrane using a varietyand quinone of different oxidoreductases, mechan whichisms. play They a key can role ‘nestle’ in the electron into the transport membrane, chains of both oxidative phosphorylation and photosynthesis, as both pathways use quinones as interacting via a hydrophobictheir electron patch carrier. Itwith should the also membrane be noted that associationinterior, of or some only peripheral associate membrane via interactions with the proteinspolar head with thegroups membrane of the is reversible,phospholipids and some [9]. PMPs Two can subsets be detached of periph- from the eral membrane proteinsmembrane which by altering we theparticularly pH or concentration, emphasize however, in thisthis is certainlyreview not are the caseli- for monotopic membrane proteins and IMPs, which are permanently attached to the pid-anchored proteins,membrane which [are10–12 anchored]. to the lipid bilayer by a special functionalized lipid embedded in the membrane,PMPs also play and a key quinone role in metabolic oxidoreductases, pathways, making which them play attractive a key propositions role in the electron transportin chains the search of for both cures oxidative for diseases phosphoryl ranging from tuberculosisation and [ 13photosynthesis,] and cancer [14–18 ]as to parasitic infections [19]. However, their highly amphipathic nature and their dependence both pathways use quinoneson lipid interactions as their iselectron what also carrier. limits both It should structure/function also be noted investigations that associ- and the ation of some peripheral membrane proteins with the membrane is reversible, and some PMPs can be detached from the membrane by altering the pH or concentration, however, this is certainly not the case for monotopic membrane proteins and IMPs, which are permanently attached to the membrane [10–12]. PMPs also play a key role in metabolic pathways, making them attractive proposi- tions in the search for cures for diseases ranging from tuberculosis [13] and cancer [14–18] to parasitic infections [19]. However, their highly amphipathic nature and their de- pendence on lipid interactions is what also limits both structure/function investigations and the ability to target them in the case of intelligent drug design [20]. There is little in- formation on the dynamic role of the membrane environment for any membrane protein, let alone PMPs. Predictably, this results in intense debate surrounding the mechanism of action or structure of many PMPs, leading to controversies in the field as in the case of Membranes 2021, 11, 346 3 of 21 ability to target them in the case of intelligent drug design [20]. There is little information on the dynamic role
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