Transmembrane Proteins Function And Structure : Detailed Facts

Transmembrane proteins or integral membrane proteins are embedded into the cell membrane and span the lipid bilayer membrane. 

These transmembrane proteins generally have three different domains: a cytosolic domain (for transmitting signals to the internal of the cell), a transmembrane domain, and an exoplasmic domain that hangs outside the cell, acting as a receptor. The chemical nature and structure of these domains vary greatly.

Still, in general, the transmembrane domain is composed of hydrophobic residues that generally adopt the configuration of either an alpha helix or a beta-sheet made up of multiple beta-strands.

Integral proteins comprise nearly 20-30% of the protein content of a cell, and these are tightly fixed in the membrane such that researchers often have to resort to more stringent conditions involving chaotropic agents like 6-8M urea, thiocyanate, lithium perchlorate or guanidinium chloride to disrupt the hydrophobic interactions of these proteins with the membrane to facilitate their extraction. 

Transmembrane Proteins Function

These proteins perform various physiologic functions in a cell, ranging from junction proteins to recognition, transport, anchorage, and transduction. 

GPCRs function in various cell signaling pathways and are one of the most critical types of receptors engaged in vast physiological processes, such as activation of transcription of certain genes in response to a ligand.

Bacteriorhodopsin is a multipass protein used by photosynthetic bacteria to capture light. Absorption of photon induces certain conformational changes in the protein, which allow it to generate a proton gradient which will eventually be utilized to synthesize ATP.


Various types of aquaporins transport molecules such as water, water-soluble molecules, and glycerol across the cell membrane.

Aquaporin 0 (a homotetramer) is the most abundant in the mammalian eye lens.

Aqua-glyceroporins are unique in transporting uncharged molecules such as urea and ammonia across the membrane. 

The outer membrane of gram-negative bacteria such as E. coli has different porins to transport different disaccharides (sugar) into the cell. 

Ion Channels

Many alpha-helix contain integral proteins from ion channels such as voltage-gated sodium ion channels, which are crucial in generating nerve impulses.

Immune cell receptors

T cell receptor contains alpha-helix and is critical for the proper functioning of the T cell responses in immunity against a disease. The same is true for the B cell receptors. 

Various enzymes in bacteria are transmembrane proteins, such as methane monooxygenase enzyme, which can oxidize the C-H bond of methane. 

Proteins targetted to various cell organelles, such as the ones targetted to the endoplasmic reticulum and others, have an enzyme called signal peptide peptidase in the cell membrane.

This enzyme recognizes the organelle-specific signal peptide in an incoming polypeptide chain and cleaves it, so it functions in the proper subcellular distribution of various polypeptide chains.

Sub cellular localisation

Proteins targeted to various cell organelles, such as the ones targeted to the endoplasmic reticulum and others, have an enzyme called signal peptide peptidase in the cell membrane.

This enzyme recognizes the organelle-specific signal peptide in an incoming polypeptide chain and cleaves it, so it functions in the proper subcellular distribution of various polypeptide chains.


Phospholipase A1 in the outer membrane of gram-negative bacteria is a type III transmembrane protein. It plays a role in various cellular activities, among which secretion of toxic peptides is one, to name a few. 

Junction Proteins

These transmembrane proteins are a crucial component of cell adhesion to the extracellular matrix and form various junctions like gaps and tight junctions between cells.

Gap junctions allow direct communication between cells. Gap junctions allow the exchange of small molecules such as ions, sugars, and amino acids. Connexin is a gap junction protein. 

Cellular recognition

Glycosylated transmembrane proteins are involved in cell recognition, and a common example is ABO blood group typing. These oligosaccharides determine a person’s blood group and are quite important clinically. 

Glucose transport

Various transmembrane proteins form different carriers and gated channels in the membrane to facilitate the diffusion of various molecules. GLUT-1 or glucose transporter 1 is one such integral membrane protein.

Transmembrane Proteins Structure

Structurally, the alpha helix is the most common structure in the transmembrane domain of integral proteins, and a partial reason for the predominance of this alpha-helix over other secondary structures is favorable hydrophobic and van der Waals interactions between lipids of the bilayer and hydrophobic amino acid residues and hydrophobic side chains of amino acids. 

transmembrane proteins function
Structure of transmembrane proteins from Wikipedia

The topology of the transmembrane proteins facing the cytosol and the extracellular matrix are different and remain the same throughout the lifetime of this protein. Peripheral proteins show flip-flop movements in a lipid bilayer, but such movements are a big no for the transmembrane proteins. 

Type I transmembrane proteins

These proteins span the membrane once.

The number of domains, especially the transmembrane domain, which ensures the stable lodging of protein in the membrane, depends greatly on the type of proteins. T

he number usually ranges from one transmembrane domain to many. Glycophorin A on the surface of RBCs is a common single-pass transmembrane protein commonly called type I transmembrane protein.

Type II transmembrane proteins

In contrast to type I proteins, G protein-coupled receptors (GPCRs) span the membrane seven times (type II transmembrane proteins) and thus are also called serpentine receptors.

Aquaporins are another example of alpha-helix containing transmembrane proteins associated with the transport of water, glycerol, and other water-soluble substances into the cell.  Hydrophobic side chains of the helix domain are excluded from the interior of the helix, and they form van der Waal interactions with the acyl chains of the lipids of the bilayer.

However, the helix doesn’t purely contain hydrophobic/uncharged amino acids. It also has hydrophilic/charged amino acids, which are engaged in hydrogen bond formation with other charged amino acids of the helix, thus helping stabilize the helix itself. 

Type II transmembrane proteins

Alpha helix might dominate the transmembrane motif in most proteins, but this is not the only motif found in an integral protein. Multiple beta strands are joined by a hairpin loop from a barrel-shaped structure called a beta-barrel which houses a cavity in the center for the transport of molecules.

It is a common secondary motif in the case of various porins. These beta barrels containing transmembrane proteins are commonly called type III transmembrane proteins. 

Structurally, these porins are homotrimers because they are composed of three identical subunits, with each subunit having 16 beta-strands forming a barrel. The interior of this porin is hydrophilic to allow the transport of hydrophilic substances into the cell; however, the exterior part of this beta-barrel is hydrophobic, and it interacts with lipids of the bilayer ensure the stability of this pore.

The unique feature of these beta-barrel proteins is an alternating arrangement of hydrophobic and hydrophilic amino acids. More than 50 such proteins contain a beta-barrel and depend upon the orientation of beta-strands. These belong to three major categories: the Greek key motif, the jelly roll motif, and the up-and-down motif. 

Type IV transmembrane proteins

Some transmembrane proteins have additional lipid anchors for further stabilization, and these are known as either type IV transmembrane proteins or lipid-anchored proteins.

The common lipid anchors include myristic acid, palmitic acid, prenylated acyl chains, and glycophosphatidylinositol (GPI).

Among these, GPI anchors are found on the cell’s exterior, that is, the exoplasmic side of the lipid bilayer but the rest of these anchors are found on the interior side of the membrane, which is the endo cytosolic leaflet of the cell membrane. 

The 5-carbon-containing isoprene is the precursor for building prenyl anchors. Bacteria lack GPI anchored proteins, but in eukaryotes such as humans, they perform a wide array of functions like receptor-dependent signal transduction, cellular adhesion, and even enzymatic functions. 


The structure of these proteins ranges from single pass to multiple pass proteins, with most of them harbouring an alpha helix as the predominant secondary structure. These proteins are involved in diverse functions, from serving as channel proteins to cell signalling.

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