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Lodish H, Berk A, Zipurskies SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.

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As we’ve checked out, all antibodies have actually a comparable structure and function; enzymes arestructurally varied, but all have a catalytic function. In comparison, although all membraneproteins are situated at the membrane, they otherwise are both structurally and functionallydiverse. As we provided in Chapter 2 and also talk about inmore detail in Chapter 5, eexceptionally biologicalmembrane has actually the very same fundamental phospholipid bilayer structure. Associated via each membrane is aset of membrane proteins that allows the membrane to lug out its distinctive activities(Figure 3-32). The enhance of proteins attached to amembrane varies depending upon cell form and also subcellular location.


Figure 3-32

Schematic diagram of typical membrane proteins in a organic membrane. The phospholipid bilayer, the basic structure of all cellular membranes, is composed of twoleaflets of phospholipid molecules whose fatty acyl tails form the hydrophobic internal ofthe (more...)

Some proteins are bound just to the membrane surchallenge, whereas others have one area buriedwithin the membrane and domain names on one or both sides of it. Protein domains on the extracellularmembrane surface are primarily involved in cell-cell signaling or interactions. Domains withinthe membrane, specifically those that form channels and pores, relocate molecules throughout themembrane. Domains lying alengthy the cytosolic challenge of the membrane have actually a wide variety of functions,from anchoring cytoskeletal proteins to the membrane to triggering intracellular signalingpathways. In many kind of situations, the attribute of a membrane protein and also the topology of its polypeptidechain in the membrane can be predicted based on its homology with another, well-characterizedprotein. In this section, we examine the characteristic structural features of membrane proteinsand also some of their basic functions. More finish characterization of the framework and functionof miscellaneous forms of membrane proteins is presented in a number of later chapters. The synthesis andhandling of membrane proteins are discussed in Chapter17.

Proteins Interact via Membranes in Different Ways

Membrane proteins have the right to be classified into 2 wide categories—integral (intrinsic)and peripheral (extrinsic)—based upon the nature of the membrane-protein interactions(check out Figure 3-32). Most biomembranes contain both typesof membrane proteins.

Integral membrane proteins, likewise calledintrinsic proteins, have actually one or more segments that are embedded in thephospholipid bilayer. Most integral proteins contain residues with hydrophobic side chains thatinteract through fatty acyl groups of the membrane phospholipids, hence anchoring the protein tothe membrane. Many integral proteins expectancy the entire phospholipid bilayer. Thesetransmembrane proteins contain one or more membrane-spanning domain names as wellas domain names, from 4 to a number of hundred residues lengthy, extending right into the aqueous medium oneach side of the bilayer. In all the transmembrane proteins examined to day, themembrane-covering domain names are α helices or multiple β strands. In comparison,some integral proteins are anchored to among the membrane leaflets by covalently bound fattyacids, as debated later. In these proteins, the bound fatty acid is installed in the membrane,yet the polypeptide chain does not enter the phospholipid bilayer.

Peripheral membrane proteins, or extrinsicproteins, do not interact via the hydrophobic core of the phospholipid bilayer. Instead theyare normally bound to the membrane indirectly by interactions through integral membrane proteins ordirectly by interactions with lipid polar head groups. Peripheral proteins localized to thecytosolic face of the plasma membrane encompass the cytoskeletal proteins spectrin and actin inerythrocytes (Chapter 18) and also the enzyme proteinkinase C. This enzyme shuttles between the cytosol and the cytosolic challenge of the plasmamembrane and also plays a function in signal transduction (Chapter 20). Other peripheral proteins, consisting of particular proteins of theextracellular matrix, are localized to the outer (exoplasmic) surchallenge of the plasmamembrane.

Hydrophobic α Helices in Transmembrane Proteins Are Embedded in theBilayer

Integral proteins containing membrane-extending α-helical domains are embedded inmembranes by hydrophobic interactions via the lipid internal of the bilayer and also probably alsoby ionic interactions via the polar head groups of the phospholipids.Glycophorin, a major erythrocyte membrane protein, exhibits both types ofinteraction. As shown in Figure 3-33, glycophorinconsists of a membrane-embedded α helix composed completely of hydrophobic (or uncharged)amino acids. The predicted length of this α helix (3.75 nm) is just adequate toexpectations the hydrocarbon core of a phospholipid bilayer. The hydrophobic side chains form van derWaals interactions with the fatty acyl chains and also shield the polar carbonyl (C=O)and imino (NH) teams of the peptide bond, which are all hydrogen-bonded to one another. Thishydrophobic helix is prevented from slipping across the membrane by a flanking set ofpositively charged amino acids (lysine and arginine) that are thneed to connect withnegatively charged phospholipid head groups. In glycophorin, the majority of of these charged residues lienearby to the cytosolic leaflet.


Figure 3-33

Amino acid sequence and also transmembrane disposition of glycophorin A from theerythrocyte plasma membrane. This protein is a homo-dimer, but only one of its polypeptide chains is displayed. Residues62–95 are hidden in the membrane, with the sequence (more...)

Many type of Integral Proteins Contain Multiple Transmembrane α Helices

Although Figure 3-33 depicts glycophorin as a monomervia a single α helix covering the bilayer, this protein is present in erythrocytemembranes as a dimer of two similar polypeptide chains. The 2 membrane-extending αhelices of glycophorin are thshould create a coiled-coil structure (check out Figure 3-9a) stabilized by certain interactions between the amino acid sidechains at the interface of the 2 helices. It is now well-known that many various other transmembraneproteins contain 2 or even more membrane-extending α helices. For circumstances, thebacterial photofabricated reactivity facility (PRC) comprises four subsystems andseveral prosthetic teams, consisting of 4 chlorophyll molecules. In this complicated protein, threeof the four subunits expectancy the membrane; 2 of these subsystems (L and M) each contain fivemembrane-spanning α helices (see Figure16-40).

A big and necessary family members of integral proteins is characterized by the visibility of sevenmembrane-extending α helices. More than 150 such “seven-spanning”membrane proteins have been established. This course of integral proteins is typified bybacteriorhodopsin, a protein discovered in a photoman-made bacterium (Figure 3-34). Absorption of light by the retinal groupattached to bacteriorhodopsin causes a conformational adjust in the protein that results inpumping of prolots from the cytosol throughout the bacterial membrane to the extracellular room.The proton concentration gradient therefore produced throughout the membrane is provided to synthedimension ATP,as discussed in Chapter 16. Both the overallarrangement of the seven α helices in bacteriorhodopsin and also the identification of a lot of ofthe amino acids deserve to be reresolved by computer evaluation of micrographs of two-dimensional crystalsof the membrane-installed protein taken at assorted angles to the electron beam.


Figure 3-34

Overall structure of bacteriorhodopsin as deduced from electron diffractivity analysesof two-dimensional crystals of the protein in the bacterial membrane. The salso membrane-extending α helices are labeled A–G. The retinalpigment is covalently (more...)

Other seven-covering membrane proteins incorporate the opsins (eye proteins that absorb light),cell-surchallenge receptors for many hormones, and receptors for odorous molecules. Amino acidsequence evaluation of these proteins has presented that no amino acids are uncovered in the sameposition in all of them, and just a few residues are conoffered in even a considerable number ofthem. Nonethemuch less, each of these proteins has salso stretches of hydrophobic amino acidslengthy sufficient (>22 amino acids) to expectancy the phospholipid bilayer. Though straight evidenceis lacking, it is assumed that all of these proteins take on a conformation in the membranecomparable to that of bacteriorhodopsin. This is just one of a number of examples of how investigators canpredict the orientation of proteins in a membrane from the amino acid sequence alone.

Multiple β Strands in Porins Form Membrane-Spanning“Barrels”

The porins are a course of transmembrane proteins whose framework differsradically from that of other integral proteins. Several types of porin are discovered in the outermembrane of gram-negative bacteria such as E. coli(view Figure 1-7a). The external membrane protects an intestinal bacterium fromharmful agents (e.g., antibiotics, bile salts, and also proteases) however permits the uptake anddisposal of small hydrophilic molecules consisting of nutrients and also waste products. The porins inthe external membrane of an E. coli cell administer channels for passage ofdisaccharides, phosphate, and similar molecules.

The amino acid sequences of porins are mainly polar and also contain no long hydrophobicsegments typical of integral proteins through α-helical membrane-covering domain names. X-raycrystallography has actually revealed that porins are trimers of similar subdevices. In each subunit 16β strands form a barrel-shaped framework via a pore in the center (Figure 3-35). As detailed earlier, fifty percent the amino acid sidegroups of a β strand also point in one direction, and also the other fifty percent point in the oppositedirection (watch Figure 3-8). Unprefer a typical globularprotein, porins have actually an inside-out setup. In a porin monomer, the outward-facing sidegroups on each of the β strands are hydrophobic and also therefore can interact through the fattyacyl groups of the membrane lipids or with other porin monomers. The side teams facing theinside of a porin monomer are mostly hydrophilic; these line the pore with whichsmall water-soluble molecules cross the membrane.


Figure 3-35

Model of the three-dimensional structure of a subunit of OmpF, a porin discovered in theE. coli external membrane. All porins are trimeric transmembrane proteins. Each subunit is barrel-shaped withβ strands forming the wall and also a transmembrane pore (more...)

Covalently Attached Hydrocarbon Chains Anchor Some Proteins to the Membrane

In eukaryotic cells, as listed previously, the polypeptide chain of some integral membraneproteins does not enter the bilayer however rather is anchored in one leaflet by a covalentlyattached hydrocarbon chain. Several widespread lipid anchors are displayed in Figure 3-36.

Figure 3-36

Anchoring of integral proteins to the plasma membrane by membrane-installed hydrocarbonteams (highlighted in red). (a) Thy-1 protein and a number of hydrolytic enzymes are anchored byglycosylphosphatidylinositol. This complex anchor is uncovered only on the (even more...)

Some cell-surface proteins are anchored to the exoplasmic face of the plasma membrane by acomplicated glycosylated phospholipid that is connected to the C-terminus. A common instance of thisform of anchor is glycosylphosphatidylinositol, which consists of 2 fatty acylgroups, N-acetylglucosamine, mannose, and inositol (see Figure 3-36a). Several enzymes, consisting of alkaline phosphatase, fall intothis course. Various experiments have presented that the phospholipid anchor is both essential andsufficient for binding these cell-surface proteins to the membrane. For instance, the enzymephospholipase C cleaves the phosphate-glycerol bond in phospholipids and also inglycosylphosphatidylinositol anchors, and treatment of cells with phospholipase C releasesglycosylphosphatidylinositol-anchored proteins such as Thy-1 protein and alkaline phosphatasefrom the cell surface.

Some cytosolic proteins are anchored to the cytosolic confront of membranes by a hydrocarbonmoiety covalently attached to a cysteine close to the C-terminus. The many widespread anchors areprenyl, farnesyl, and also geranylgeranyl teams. These proteins undergo a chemical modificationinvolving several procedures. First, the anchor moiety develops a thioether bond through the thiol groupof a cysteine that is four residues from the C-terminus of the protein. The modified proteinthen undergoes proteolysis and also methylation; these reactions remove the 3 terminal residuesand also include a methyl to the new C-terminus. In some situations, fatty acyl palmitate teams formthioester bonds to nearby cysteine residues, offering additional anchors that are assumed toreinforce the attachment of the protein to the membrane (see Figure 3-36b).

In an additional group of lipid-anchored cytosolic proteins, a fatty acyl group (e.g., myristate orpalmitate) is attached by an amide bond to the N-terminal glycine residue (check out Figure 3-36c). In these proteins, the N-terminal anchor isvital for retention at the membrane and also may play a crucial role in a membrane-associatedfunction. For example, v-Src, a mutant develop of a cellular tyrosine kinase, is oncogenic and also cantranscreate cells just when it retains a myristylated N-terminus.

Some Peripheral Proteins Are Soluble Enzymes That Act on Membrane Components

An vital group of peripheral membrane proteins are water-soluble enzymes that associatewith the polar head teams of membrane phospholipids. One well-construed team of such enzymesare the phospholipases, which hydrolyze assorted bonds in the head teams ofphospholipids (Figure 3-37). These enzymes have animportant duty in the deterioration of damaged or aged cell membranes.

Figure 3-37

Specificity of cleavage of phospholipids by phospholipases A1,A2, C, and D. Susceptible bonds are shown in red. R denotes the polar group attached to the phosphate,such as choline in phosphatidylcholine (see Figure5-27a) or inositol in phosphatidylinositol. (even more...)

The system of action of phospholipase A2 illustprices exactly how such water-solubleenzymes have the right to reversibly interact through membranes and also catalyze reactions at the interchallenge of anaqueous solution and lipid surconfront. When this enzyme is in aqueous solution, itsCa2+-containing active site is hidden in a channel lined with hydrophobicamino acids. Binding of the enzyme to a phospholipid bilayer induces a little conformationalchange that fixes the protein to the phospholipid heads and opens the hydrophobic cleft. As aphospholipid molecule moves from the bilayer into the channel, the enzyme-boundCa2+ binds to the phosphate in the head team and positions the ester bondto be cleaved beside the catalytic website.

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