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11.1: Membrane and Membrane Proteins

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    14983
  • One easily understandable function of membrane bilayers is to separate the inside and outside of the cell or intracellular organelles.  Yet as we mentioned before, such barriers can not be so rigid and impenetrable that they prevent movement of materials across the membrane.  Also, all cells must sense and respond to their environment through a process called signal transduction.   We have already discussed lipid molecules involved in signaling.  Now let's turn our attention to proteins that associate with the membrane and confer added functionalities to it.  Figure \(\PageIndex{1}\) below reviews some of the features of membranes we've discussed before and show a simple bilayer (top) to the complicated membrane/cell wall of bacteria.

    membsimplecomplex.svg

    Figure \(\PageIndex{1}\): Membrane from simple to complex

    Types of Membrane Proteins

    Although we presented this image earlier, Figure \(\PageIndex{2}\) below reviews the details that should now be clearer to you.  In this section, we will explore membrane proteins in more detail.

    0303_Lipid_Bilayer_With_Various_Components.jpg

    Figure \(\PageIndex{2}\):  A cell membrane with periipheral and integral membrane proteins. https://commons.wikimedia.org/wiki/F...Components.jpg.  This file is licensed under the Creative Commons Attribution 4.0 International license.

    Proteins can be loosely associated with the membrane (peripheral or extrinsic), or can  imbed deeply and most typically pass through the membrane and become atransmembrane (also called integral or intrinsic) protein. Sometimes they pass through using a single alpha helix, while other time they pass through multiple times (for example seven times in G-protein coupled receptors).  They can also be classified based on the number of leaflets of the membrane they cross, as shown in Figure \(\PageIndex{3}\) below.

    topicity.svg

    Figure \(\PageIndex{3}\):  Peripheral and biotopic, monotopic, and polytopic integral membrane proteins

     

    Peripheral Proteins

    The proteins interact with a membrane through protein-lipid head group interactions, but might slightly penetrate the membrane. Those that do would be classified as monotopic peripheral.  Peripheral proteins are generally easy to remove from a membrane in vitro by changing solution concentration of ions as the interactions are often ion-ion nature.  The first model below shows the binding of a matrix metalloproteinase (MPP) 12 to a lipid bilayer.  This protein is involved in inflammation, wound healingarthritis, cardiovascular disease and remodeling of neural synapses, suggesting a broad role in recovery from cell and tissue abberations.  MMP-12 is secreted by macrophages so it is considered a water soluble (aqueous) protein.  It travels to viral cells and appears to display activity not in aqueous solution but near membranes, implying activation of the enzyme through binding to the bilayer. 

    Studies show the catalytic domain of MPP 12 can bind bilayers through both α- and β- secondary structure regions of the protein.  Figure \(\PageIndex{4}\) below shows an interactive iCn3D model of the protein and its interaction with the membrane through alpha-helical region.  Once bound to the membranes, catalytic activity increases.

    matrix metalloproteinase (MPP) 12 _lipid bilayer..png

    NIH_NCBI_iCn3D_Banner.svg Figure \(\PageIndex{4}\): Catalytic domain of peripheral membrane  Protein MPP 12 Interacting with a bilayer.. (Copyright; author via source).  Click the image for a popup or use this external link: (not available)

    Other MMP localize to membranes in other ways.  MMP-7 interacts with heparan sulfate proteoglycans (CD44) and lipid rafts. Others bind transmembrane proteins  like integrins.  

    Another examples of peripheral protein include many precursor forms of protein clotting factors.  Clotting is initiated when the serine protease thrombin cleaves fibrinogen to form fibrin, which self-associate to form a fibrin clot, or when thrombin activates receptors in platelets.  The soluble precursor of thrombin, prothrombin, a zymogen, is activated on membrane binding through interactions with several proteins assembled on a negatively charged phospholipid  (like phosphatidylserine) bilayer in the prothrombinase complex.  How does the precursor zyymogen interact with membrane?  It requires calcium ions, which binds to a series of gamma-carboxylated gluatamic acid (GLA) residues on the zymogen.  The enzyme that carboxylates the zymogen depends on Vitamin K. 

    Here is a model (1NL2) of bovine prothrombin Fragment 1 (N terminal) bound to a bilayer through  its GLA domain.

    Figure \(\PageIndex{5}\) below shows an interactive iCn3D model of bovine prothrombin Fragment 1 (N terminal) bound to a bilayer through  its GLA domain (1NL2). 

    Bovine prothrombin Fragment 1_ bilayer_GLA domain (1NL2).png

    NIH_NCBI_iCn3D_Banner.svg Figure \(\PageIndex{5}\): Bovine prothrombin Fragment 1 (N terminal) bound to a bilayer through  its GLA domain (1NL2). (Copyright; author via source).  Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...SG6qByvpAsvwe6

    Click on this link to see a zoom view of just the calcium ions and Gla sidechains: https://structure.ncbi.nlm.nih.gov/i...xydtj8a4WHgdb7

    The Gla domain in the absence of calcium ions is disordered.  On binding, an ordered linear alignment of bound calcium ions is formed, stabilizing the ordered structure of the Gla domain and allowing interaction with the membrane.  Three nonpolar amino acid side chains, Phe 5, Leu 6 and Val 9, are now clustered and exposed, allowing penetration of this hydrophobic patch part way into the membrane.  They are represented in cyan spacefill just underneath the surface of the red dots in the model above (the red dots are dummy atoms which represent the outer bilayer leaflet). Given this penetration, this protein domain would then be considered monotopic.

    What is not shown in the model is the role of negatively charged phosphatidyl serine.  Studies have shown that head group of serine in lysophosphatidyl serine (which has only one acyl group) provides additional ion-ion interactions with the Ca2+ ions that also bind Gla residues 17 and 21. Arg 10 and Arg 16 also interact with the phosphatidly serine head group.  Phosphatidylcholine could also spatially fit into the active site but electrostatic interactions would prevent it.  Why?

    Lipid-Anchored Proteins

    We have studied lipids, proteins, and carbohydrates. Although phospholipid can spontaneously form bilayers, the actual structure of biological membranes is made much more complicated through addition of protein and carbohydrate substituents to the membrane. Soluble proteins can be made to insert into bilayers by addition of nonpolar attachments. Localization to a membrane changes the functional expression of the protein.  Several examples of such attachments are described below.

    Fatty acid linkers

    Two common covalent modification of proteins are N-myristoylation (attached myristic acid - 14:0 - through an amide link) and S-palmitoylation (attached palmitic acid - 16:0 - through a thioester link with a Cys),  

    Myristolation is usually a cotranslational modification in eukaryotic and viral proteins that occurs after cleavage of the N-terminal methionine.  The figure below shows an image of a N-terminal glycine myrisotolated protein, 1A6Q CRYSTAL STRUCTURE OF THE PROTEIN SERINE/THREONINE PHOSPHATASE 2C AT 2 A RESOLUTION. 

    insert when Charmm GUI works

    This modification is a key part in initiating immune system signal transduction pathways.  The modification is catalyzed by N-myristoyltransferase (NMT) using myristoyl-coenzyme as the fatty acid acyl donor. This activates function of the protein in part through reducing the dimensionality of substrate diffusion to the protein to the 2D surface of the membrane instead of a 3D search in the cytoplasm.  NMT acylates protein at this general consensus sequence:  G1X2X3X4S/T5X6R7R8 .

    Likewise, many signaling proteins are palmitoylated. leading to protein recruitment to membranes.  Small G proteins like Ras, Rho and the alpha subunit of heterotrimeric G proteins are often palmitoylated. This modification is also be found in transmembrane proteins in which localization is not an issue (see example xx below).  In such circumstance, the modificaiton might however help in targeting the proteins to rafts within the membrane.  Palmitic acid is saturated and addition of it to a protein might target it to more ordered regions of the membrane with cholesterol and sphingholipids within rafts. 

    Isoprenoids linkers:

    The isoprenoids farnesyl (15C) or geranylgeranyl (20C)are added to a CAAX carboxy-terminal sequence in target protein like RAS, where C is Cys, A is aliphatic, and X is any amino acid, which helps target proteins to the membrane.  The enzymes used for these modifications are farnesyltransferase (FTase) and protein geranlygeranyltransferase
    I (GGTase I), respectively.  For this and the other modifications, it has the potential to do more than target proteins to the membrane.  The modification can also modulate protein-ligand interactions and protein stability.  Ras, a key signaling protein, is a target of prenylation.

    Ras and other small G proteins are involved in a large percentage of human cancers.  As the G protein Ras has somewhat of a billiard ball surface with obvious sites to target drugs that would affect its aberrant function in cancers, efforts have been made to target the prenyl transferases necessary to target it to the membrane.

    In humans there are 3 different gene in the Ras family, H-Ras and N-Ras, whose gene products localize to both plasma and Golgi membranes, and K-Ras, which localizes predominantly to the plasma membrane.  These and other G proteins bind GTP and possess GTPase activity.  The GTP bound form is active, while the GDP form is inactive.  Point mutations that attenuate or prevent GTP cleavage leave the protein continually activated which contributes to ongogenesis.  

    KRas has two predominant isoforms, 4A, the canonical form (also called 2A) and 4B (also called 2B) that arise from alternative splicing of the primary RNA transcript.  The C-terminal protein sequences of isoform 4A and 4B differ significantly.

    Isoform 4A: QYRLKKISKEEKTPGCVKIKKCIIM

    Isoform 4B: KHKEKMSKDGKKKKKKSKTKCVIM

    The farnesylation motif site containing the modifed Cys are highlight in yellow above.  The same cysteine is also often carboxymethylated.  The Cys six residues from the farnesylated Cys in isoform 4A is also often palmitoylated

    Figure \(\PageIndex{6}\) below shows isoform KRas 4B bound to a membrane bilayer through its farnesylated tail.  (PDB file provided by Alemayehu (Alex) Gorfe. Viney Nair and Andrew McCammon). The tail is essential for its function at the plasma membrane where KRAS-mediated signaling events occur. Phosphodiesterase-δ (PDEδ) binds to KRAS4b and plays an important role in targeting it to cellular membranes.  Note that the farnesyl attachments only penetrates into part of the upper leaflet.

     

    wholeKRasMembrane.svg

    Figure \(\PageIndex{6}\): Isoform KRas 4B bound to a membrane bilayer through its farnesylated tail

     

    Glycosyl-phosphatidylinositol linkers

    Normally soluble cytosolic proteins can become attached to membranes through addition of a glycosyl phophatidylinositol (GPI).  The attachment usually contains a conserved tetrasaccharide core of three mannoses (Man) and one unacetylated glucosamine (GlcN) linked to the carboxy-terminus of the protein. The GPI can be further modified with extra galactoses and mannoses, as well as additions to the PI group, which secures the protein in the membrane. Figure \(\PageIndex{7}\) below shows the common backbone for GPI anchors.  Note the additions of the phosphoethanolamines to the core polysaccharide.

    GPI_ANCHOR_CoreandMammalian.svg

    Figure \(\PageIndex{7}\):  Common backbone of GPI anchors  

    GPIs are found in eukaryotic cells, and link many surface antigens, adhesion molecules, and hydrolases to the membrane. GPIs from Plasmoidium falciparum, the malarial parasite which kills about two million people each year, appears to act as a toxin and is the most common CHO modification of the parasite protein. Mice immunized against the GPI sequence, NH2-CH2-CH2-PO4-Man (α1-2) 6Man (α1-2) Man (α1-6) Man (α1-4) GlcNH2 (α1-6) myo-inositol-1,2-cyclic-phosphate, were substantially protected from malarial symptoms and death after they were exposed to the actual parasite.

    Figure \(\PageIndex{8}\) below shows a cross section of a membrane (with cholesterol, PE, SM) containing the glycosylated form of the human complement regulatory protein CD59 protein (1cdr) with a GPI anchor attached at its C-terminus. Note that the the middle part of the anchor (glycan) holds the actual protein well above the top of the lipid bilayer.  The soluble protein is also glycosylated.  The protein binds to complement proteins C8 and/or C9, which are effector immune proteins that assemble on the surface of a cell undergoing lysis. 

    1cdrwithGPIAnchorSmallPatch.png

    Figure \(\PageIndex{8}\):  Cross section of a membrane containing the glycosylated form of the human complement regulatory protein CD59 protein (1cdr) with a GPI anchor attached at its C-terminus

    The GPI anchor is shown in spacefill.  Note that it only extends halfway into the bilayer, as you would expect from the size of the fatty acids attached to the phosphatidyl inositol.  The glycan part of the GPI is shown in spacefill between the lipid and its protein attachment site.  The protein is also glycosylated in the extracellular domain.

    Something new!

    A new (5/21) and totally unexpected type of glycosylated molecule has been found at the outer leaflet of mammalian cells - a glycosylated RNA, as shown in Figure \(\PageIndex{9}\) below.  This adds RNA to the lipids and proteins as a target for glycosylation. These surface glycoRNAs interact with antibodies again ds-RNA and the Siglec lectin family.  They are found in cells in vivo and in cultured cells in vitro.

    RNAGlycan.svg

    Figure \(\PageIndex{9}\): A glycoRNA - a small noncoding RNAs with sialylated glycans. Flynn et al., Small RNAs are modified with N-glycans and displayed on the surface of living cells, Cell (2021), https://doi.org/10.1016/j.cell.2021.04.023

    Transmembrane (Integral) Proteins

    These proteins pass through the membrane either one in one pass, usually with a single alpha-helix, or many membrane-spanning helices.  For example, G protein coupled receptors, often called serpentine receptors, cross the membrane seven times.   There are three different types based on the number of types the protein crosses the membrane and the type of secondary structure used in crossing: biotopic (single pass), alpha-helical polytopic, and beta-barrel.  These proteins are found in all types of membranes and have many types of functions, from receptors, receptor ligands, structural, adhesion, transport, gene regulation and transport. 

    Transmembrane Biotopic - Single Pass Proteins

    The are 4 types of single-pass transmembrane proteins:

    • Type I: N-terminal outside of the cell (extracellular) and the precursor signal sequence on the N-terminus which is a localizatiion sequence is removed
    • Type II: N-terminal intracellular and with the transmembrane domain closes to the N-terminus
    • Type III: N-terminus extracellular and no signal sequence in precursor protein
    • Type IV: N-terminus intracellular and the transmembrane domain close to the C-terminus

    The transmembrane domain of single-pass integral membrane proteins consist of a single alpha-helices with nonpolar side chains extending outward from the helical axis where they interact with the nonpolar lipid parts of the membrane.  These nonpolar sides are more stable in nonpolar environments. 

    To study such proteins in less complex environment, membranes are often "dissolved" in nonpolar, single chain amphiphilc detergents.  These single chain amphiphiles form micelles in the absence of membrane proteins, but can form mixed micelles in which the nonpolar part of the protein is surrounded in the detergent micelle by the nonpolar acyl chains of the detergent.

    Figure \(\PageIndex{10}\) (top) below shows just the transmembrane and juxtamembrane (next to the membrane) domains of the single pass Notch protein, which is critical in many signal transduction pathways.   

    protein_5KZO_OG_singlehelixpassMultRep_OG_micelle.svg

    Figure \(\PageIndex{10}\):  Transmembrane and juxtamembrane  domains of the single pass Notch protein in a bilayer and an octylglucoside micelle

    The top images in the figure above show different ways to represent the protein in the bilayer, with the right hand image showing a cross-section through the membrane so as to better show how the protein passes through the bilayer.  

    The bottom images  in the figure above shows the protein after excess detergent, in this case octylglucoside, is added to the protein-containing bilayer. 

    Here are some examples of bitopic single-pass transmembrane proteins

    Cadherins

    All structures need support and connections.  At the macro level, the skeleton supports the mass and organization of organs and tissues in whole organisms.  Within an organ, how car cells held together?  How do they adhere to each other.  Certainly not through outer leaftlet lipid contacts as the outer surface of the leafet is typically charged.  The extracellular matrix does provide some of the glue that holds cells together.  At a more detailed level, transmembrane protein are involved.  One class of adhesive proteins are the cadherins, calcium-dependent cell adhesion molecule. There are over 100 human cadheins.  They are mostly ditopic, single transmembrane pass proteins.  Their cytoplasmic domains interact with proteins like catenin, which then bind to the interior cytoskeletal network composed of actin and other proteins. This provide a way for the intracellular region to regulate the extracellular interactions of the cell.

    The extracellular domain is composed of five repeating "cadherin" domains, each around 110 amino acids, that can fold independently.  Calcium ions bind at the domain interfaces. A cadherin can interact with other cadherin domain on other cadherins on other cells, leading to cell adhesion.  Essentially, the receptor cadherin on one cell binds the ligand caderin on the other.  As metastatic tumor cells loose their adhering feature and leave the site of the primary tumor, you would expect that mutations in cadherins are often involved. The may also be involved in cell sorting during morphogenesis, "regulation of tight and gap junctions, and in the control of intercellular spacing".

    Figure \(\PageIndex{11}\) below shows a "constructed" image of cadherin-1 (1L3W) interacting with cytoplasmic β-catenin (1I7X) through a modeled transmembrane helix (amino acids QIPAILGILGGILALLILILLLLLFLRR, amino acids 706-731).  No full length structure of a  cadherin in a membrane is available.

     

    Cadherin1.svg

    Figure \(\PageIndex{11}\): A constructed" image of cadherin-1 (1L3W) interacting with cytoplasmic β-catenin (1I7X) through a modeled transmembrane helix

    Membrane Protein Kinases

    Kinases are enzymes that phosphorylate substrates.  Hexokinase is a protein enzyme that catalyzes the phosphorylation of a hexose substrate such as glucose.  A protein kinase is a protein enzyme that phosphorylates a protein substrate.  That protein could be another copy of itself  or another protein.  We will see in Chapter 12 that many protein kinases are involved in cell signaling.   Many tyrosine protein kinases are bitopic single pass integral membrane proteins that become active on binding a ligand. Typically, on binding a extracellular ligand, two monomeric copies of the kinase form a dimer in the membrane, activating a tyrosine kinase cytoplasmic domain, which typically phosphorylates (using ATP as a substrate) the other member of the dimer in an "autophosphorylation" reaction.  Sometimes the dimers are held together by disulfide bonds.

    Figure \(\PageIndex{12}\) below shows a "constructed" image of the human dimeric insulin receptor. 

    insulinreceptorTotal.svg

    Figure \(\PageIndex{12}\): aA "constructed" image of the human dimeric insulin receptor

    One of the monomers is shown in gray.  The other monomer is shown in colors corresponding to the domain organization of the protein.  Each extacelluar dimer (6PXV) has two insulins bound (yellow spacefill).  The intracellular domains (1IR3) are activated on insulin binding.  No full length structure of full insulin receptor in a membrane is available.

    Almost half of all helical membranes proteins in humans are biotopic, compared to between 20-25% in prokaryotes. Humans have 10-20 fold more bitopic proteins than does E.Coli.  There appear to be about 196 biotopic proteins in E. coli (located in the inner membrane ) and 70 in M. jannaschii (Archea in plasma membrane).   In humans, 57% are in the plasma membrane, with the rest distributed between the Golgi, ER, nuclear, mitochondrial and chloroplast membranes.  In single-celled yeast, only 8% are in the plasma membrane.

    Beta-Dystroglycan

    This protein is another example of a biotopic protein with a single alpha-helix membrane domain.  Dystroglycan is a dimer of alpha and beta subunits.  Alpha-dystroglycan is a peripheral protein that binds beta-dystroglycan, a transmembrane protein.  Alpha dystroglycan also binds lassa virus and lymphocytic choriomeningitis virus glycoprotein, as it serves as a viral receptors.  It also binds the protein dystrophin, a protein missing in Duchenne muscular dystrophy, bwhich affects 1 out of 5000 live male births.  As an integral transmembrane protein, beta-dystroglycan connectxthe extracellular matrix to the cytoskeleton through dystrophin. Alpha- and beta-dystroglycan share the same gene, which codes one long protein which is proteolyzed post-translationally to form the alpha (N-terminal end) and beta subunits (C-terminal end).

    Figure \(\PageIndex{13}\) shows a schematic outline of dystrophin and the dystrophin-associated glycoprotein complex (DAGC). 

    Animal_models_of_Duchenne_muscular_dystrophy_FromFig1_.svg

    Figure \(\PageIndex{13}\): Schematic outline of dystrophin and the dystrophin-associated glycoprotein complex (DAGC). Dystrophin contains N-terminal (NT), middle rod,
    cysteine-rich (CR) and C-terminal (CT) domains. The middle rod domain is composed of 24 spectrin-like repeats (numerical numbers in the cartoon, positively
    charged repeats are marked in white color) and four hinges (H1, H2, H3 and H4). Dystrophin has two actin-binding domains located at NT and repeats 11-15,
    respectively. Repeats 1-3 interact with the negatively charged lipid bilayer. Repeats 16 and 17 form the neuronal nitric oxide synthase (nNOS)-binding domain.
    Dystrophin interacts with microtubule through repeats 20-23. Part of H4 and the CR domain bind to the β-subunit of dystroglycan (βDG). The CT domain of
    dystrophin interacts with syntrophin (Syn) and dystrobrevin (Dbr). Dystrophin links components of the cytoskeleton (actin and microtubule) to laminin in the
    extracellular matrix. Sarcoglycans and sarcospan do not interact with dystrophin directly but they strengthen the entire DAGC, which consists of dystrophin,
    DG, sarcoglycans, sarcospan, Syn, Dbr and nNOS. .Disease Models & Mechanisms (2015) doi:10.1242/dmm.018424vailable via license: CC BY 3.0

     

    Transmembrane - Alpha-helical polytopic 

    There are so many intriguing examples of these proteins.  We'll illustrate just two.

    Rhodopsin-like receptors and pumps

    These proteins are involved in cell signaling and are the target of most pharmaceutic drugs.  G protein coupled receptors (GPCRs) are incredibly important and we will discuss them extensively in Chapter 12.

    GPCRs are cell receptors receptors which span the membrane seven times in a serpentine fashion.  They bind ligand (neurotransmitter, hormones, etc) in the extracellular or internal membrane domains (the latter for hydrophobic ligands) and through propagated conformations changes alter the cytoplasmic domain where they functionally interact with a heterotrimeric G protein.  

    Figure \(\PageIndex{14}\) below shows an interactive iCn3D model of the human cannaboid receptor with a bound cholesterol and Δ -tetrahydrocannabinol (Δ-THC) in spacefill (5xra).  The red dummy atoms represent the outer leaflet and the blue the inner.

    Human cannaboid receptor _ cholesterol_THC(5xra).png

    NIH_NCBI_iCn3D_Banner.svg Figure \(\PageIndex{14}\): Human cannaboid receptor with a bound cholesterol and Δ -tetrahydrocannabinol (Δ-THC).  (5xra). (Copyright; author via source).  Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...PaTFrkGFgKeP2A

    Δ -THC is a partial agonist and turn on the response of the receptor.  The active site is conformationally somewhat flexible or plastic.  Other ligands bound to it act as antagonists instead of agonist and must do so by eliciting nonactive conformations. 

    ABC Transporter

    Figure \(\PageIndex{15}\) below shows an interactive iCn3D model of the  P-glycoprotein multidrug resistance transporter protein (6nf1).

    P-glycoprotein multidrug resistance transporter protein (6nf1).png

    NIH_NCBI_iCn3D_Banner.svg Figure \(\PageIndex{15}\):  P-glycoprotein multidrug resistance transporter protein (6nf1). (Copyright; author via source).  Click the image for a popup or use this external link:https://structure.ncbi.nlm.nih.gov/i...zzXduCZjhCMaw9

     

    The spacefill ligands represent Zosuquidar, which binds with high affinity to P-glycoprotein and inhibits its activity, making  it a cancer agent as it prevents chemotherapeuitc drugs that have entered the cell from being pumped out. The protein chain interacting with it on the cytoplasmic face is an antibody fragment used to stabilize the P-glycprotein so crystals could form.

     

    Transmembrane Beta-barrel transmembrane 

    We will focus on two of these proteins.

    Outer Membrane Factor (OMF) - Gram negative bacteria

    Figure \(\PageIndex{16}\) below shows an interactive iCn3D model of  a beta-barrel transmembrane protein OPRM - Outer Membrane Factor (4y1k) from Pseudomonas aeruginosa that acts as a pore.  It also has a palmitoyl fatty acid in thioester linkage to Cys 1 of the protein for extra but unneeded anchorage.  

    Bbeta-barrel transmembrane protein OPRM _Pseudomonas aeruginosabeta-(4y1k) .png

    NIH_NCBI_iCn3D_Banner.svg Figure \(\PageIndex{16}\): Beta-barrel transmembrane protein OPRM - Outer Membrane Factor (4y1k) from Pseudomonas aeruginosa  (4y1k).  (Copyright; author via source).  Click the image for a popup or use this external link:https://structure.ncbi.nlm.nih.gov/i...xrAuW1oFtY5FL7

    Use this link for another view:  https://structure.ncbi.nlm.nih.gov/i...FtY5FL7&t=4Y1K (OPM) in iCn3D

    This protein is part of a large complex of proteins that spans both the inner and outer membranes of Gram negative (examples E. Coli and Pseudomonas aeruginosa) bacterial cell walls.  Unfortunately for humans, this protein complex pumps out toxins (to the bacteria) like antibiotics, which makes bacteria resistant to these drugs. The OPRM acts as the outer passage way or duct for the pumped molecules.  Bacterial Outer Membrane Factor (OMF) protein differ in sequence but all form the beta-barrel duct.  The E. Coli version of OMF has a triacylated lipid modification of the N-terminus.  The N terminal lipid modification might be necessary for initial attachment of the protein to a membrane before insertion of the beta-barrel. As such, the enzymes involved in the attachment of the tail could be targets for new antibiotics.

    Voltage-dependent anion channel (VDAC) - mouse

    This protein regulates the movement of molecule between the cytoplasm and interior of the mitochondria across the outer mitochondrial membrane. VDAC also serves as a docking site or scaffold for the assembly of molecule into a complex that regulates mitochondrial function.  The protein's conformation and hence function is regulated by changes in the transmembrane potential, which we will explore in the next sections.  Hence the protein and its function are voltage-dependent. Figure \(\PageIndex{17}\) below shows an interactive iCn3D model of mouse VDAC with a beta barrel formed by 19 beta-strands (3emn).

    VDAC_mouse_3EMN.png

    NIH_NCBI_iCn3D_Banner.svg Figure \(\PageIndex{17}\): Mouse voltage dependent anion channel (VDAC) (3emn).  (Copyright; author via source).  Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...WxUqWaGPxgHH79

    Note the N-terminal alpha-helix resident inside the channel opening.  This helical section moves on changes in membrane potential, gating open and hence regulating the flow of metabolites and ions across the membrane through the pore.  At a low transmembrane potential (10 mV), the conductance is high as the channel is in the open state.  When the potential increases to 30 mV (either + or -) conductance drops as the protein forms the closed state.

    Now that you understand the structure of membrane proteins, let's explore a key type of function of a subset of integral membrane proteins: movement of molecules/ions across the membrane.