Nuclear envelope proteins; typical animal cell


Three reasons nuclear envelope proteins glide into the nucleus effortlessly

By Juman Hijab

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Original date: May 14, 2023  

Updated: May 14, 2023

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Nuclear envelope proteins; typical animal cell

Alila Medical Media. Typical animal cell, with endoplasmic reticulum shown., ID: 112395266.  A typical cell, labeled

Nuclear envelope proteins

Cellular membrane proteins are generated through the help of membrane-bound ribosomes in the rough endoplasmic reticulum (RER) (1, 2).

These integral membrane proteins  are free to diffuse laterally through the membranes of the endoplasmic reticulum system - both the rough and the smooth (SER) (which is ribosome-less) - as if they are swimming in water park canals that meander throughout the cytoplasm.

Some of those proteins float their way into the membranes encircling the nucleus; They end up as nuclear envelope proteins.

Nuclear envelope proteins provide direct connections to the outside of the cell

Why is this important?

Because nuclear envelope proteins create direct connections between the components of the nucleoplasm (DNA, histones, etc) and the cytoplasm (and thus to the outside of the cell). If the connections are diseased, the cell's internal and external signals give faulty information to the nucleus and the cell is no longer healthy. For example, striated muscle laminopathies (involving skeletal and cardiac muscle) are the result of genetically defective nuclear envelope proteins (3).

Gliding through the nuclear pore to reach the inside of the nucleus

The nuclear envelope is a double-membraned structure. The outer nuclear membrane (ONM) is an extension of the RER.

Thus, the ONM is also studded with ribosomes. The inner nuclear membrane flattens itself on the inside of the outer membrane while keeping a space of 30 - 50 nanometers wide.

While many of the proteins in the RER, the outer nuclear membrane, and the SER are the same, the inner nuclear membrane manages to establish a unique grouping of membrane proteins.  The reason behind this is that only certain membrane proteins are allowed to glide through the nuclear pores in the nuclear envelope to reach the inner nuclear membrane sanctity.

Nuclear envelope proteins

Dabilg. Structure of eukaryotic cell nucleus, nuclear pore, envelope and nuclear lamina., ID: 2201179499

The nuclear pore "gates"

Let me describe the nuclear pores. The double-membraned nuclear envelope has holes within it that seemingly create a conduit between the cytoplasm and the nucleoplasm. However, those conduits do not provide free passage; they are studded with proteins that form the nuclear pore complex (NPC). The proteins of the NPC are selective, acting like brambles guarding entry into the nucleus. 

In fact, passage through those nuclear pore "gates" requires chaperones (3, 4). For example,  karyophorin proteins act as chaperones helping histones, transcription factors, and enzymes make their way into the nucleoplasm (4). 

What about the membrane proteins in the RER? How do the outer nuclear envelope proteins glide past the brambles of the nuclear pore and end up on the inner nuclear membrane?

They do this because of three factors that allow them to sneak in. 

Basic or hydrophobic tails

Small proteins (under 9 nanometers) can passively diffuse into the nucleus. However, others - including membrane proteins need something to shepherd them in.

Proteins destined to the nucleus have Nuclear Localization Signals (NLS) that are a string of basic amino acids at the ends of the protein (5, 6). It is as if the protein has flashing lights at its end. Those NLS's arginines and lysines help the proteins attract and bind to chaperone proteins. The tagged and bound proteins are sneaked through the nuclear pores to the nucleoplasm.

Cancer and Amyotrophic lateral sclerosis (ALS)

Dysfunctional localization of proteins (nucleus v/s cytoplasm) clearly leads to disease. For example, some proteins have a function in preventing cancer (p53 tumor suppressor, nucleophosmin, and retinoblastoma (Rb) proteins) (7). Those proteins have the requisite NLS sequences of basic amino acids and set up residence in the nucleus.  Unfortunately, though, in some cancers,  those proteins are either inactivated or mutated leading to a cytoplasmic localization. This does not help the cell maintain healthy tumor-suppressor processes.

In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, a protein named TDP-43 also has NLS sequences and lives primarily in the nucleus. However, in those two diseases, there is dysfunctional binding of the protein with the karyophorins, leading to aggregates of tangled proteins in the brain cells' cytoplasm (8). 

RER membrane proteins that travel to the nucleus

Thus, many proteins destined to reside in the nucleus have basic amino acid sequences in their protein tails. When proteins float over from the RER membranes, they are directed to the inner nuclear membrane. 

Inner nuclear membrane proteins (for example, Emerin, Lamin Binding Receptor (LBR), lamina-associated polypeptide 2 (LAP2), Sad1-UNC84 domain containing 1 (SUN1/2), and MAN1) all have nuclear localization signals  (9, 10).

Inner membrane nuclear proteins

Hijab J. Schematic drawing of prominent inner membrane nuclear proteins (Lamin Binding Receptor (LBR), lamina-associated polypeptide 2 (LAP2), Sad1-UNC84 domain containing 1 (SUN1/2),The N at the end of the protein denotes the amino-terminal (NH2); the C denotes the carboxyl-terminal (COOH) May 2023

Small or compact heads

The second factor that helps RER membrane proteins make it through the nuclear pore to the inner nuclear membrane is that they have relatively compact heads. If you look at the schematic image above, you can see that there is not a lot of amino acid groups sticking out into the lumen of the nuclear envelope (except for SUN1).

Many of the inner nuclear membrane proteins have sequences of amino acids that are firmly attached to the transmembrane amino acids. Thus, LBR, Nurim, and Man1 have both the amino- ("N") and carboxyl- ("C") terminals of their peptide residing in the nucleoplasm. This allows the protein to sneak past other proteins in the peri-nuclear space, because they have their "backs" turned away from the proteins within that space. 

The table below shows the estimated number of amino acids in the nucleoplasm and (when applicable) the nuclear envelope lumen - the peri-nuclear space ( and 9). 

Nuclear proteins

Hijab J. Inner membrane nuclear proteins, May 2023

Note that the table shows (except for SUN1) that the inner membrane proteins have both their "hands" (amino (NH2)-terminal) and "feet" (carboxyl (COOH)-terminal) away from the lumen of the nuclear envelope (LBR, Man1, Nurim, and LUMA) or they have only a small number of amino acids within that lumen (Emerin, Lap2).

Given that the limited lumen sequences are less likely to form connections with other proteins within the peri-nuclear space, the protein easily sneaks its way around the corner of the nuclear pore with the help of chaperone proteins binding its nucleoplasm-based amino acid segment. The whole protein glides effortlessly from the outer nuclear envelope, past the nuclear pore, to position itself on the inner nuclear membrane.

Getting front row seats to DNA

Landing onto the inner nuclear membrane means that the protein now has front row seats to the chromatin (DNA and protein complex) and the RNA in the nucleus.

Proteins that have basic amino acids avidly bind to histones (proteins within the nucleus) and DNA. Thus, LBR's amino-terminal has many basic amino acid side groups (1, 11). This encourages it to be chaperoned into the nucleus and then binding it to chromatin. In fact, even a shortened LBR protein will land into the inner nuclear membrane, as long as it has that amino-terminal as part of the protein.

Placing specific proteins in the inner nuclear membrane means that the nucleus can organize its closets. Chromatin needs to be segregated in the nucleus. Thus, heterochromatin attaches to the nuclear envelope through the LBR protein. Young or cancerous cells are dependent on LBR's help. When the cell ages, there is down-regulation of the protein, and dysfunctional tethering of DNA to the nuclear envelope (11, 12, 13). Many of those interactions between a protein's basic amino acids are with the phosphate groups of the nucleic acids of DNR and RNA, primarily hydrogen bond interactions (14). 

 Clearly, having basic amino acids, particularly arginines, in the segments of the inner membrane protein that anchor in the nucleoplasm is critical. Those highly basic peptide segments connect with the DNA and RNA in the nucleus (5). The more basic, the better (15).

Conclusion: Nuclear Envelope Proteins

Proteins that are destined to reside in the nucleus have inbuilt amino acids (usually basic ones, like arginine and lysine) that give them the key to gliding through the nuclear pore and gaining entry to the nucleoplasm.

In addition to diseases that are related to dysfunctional localization of proteins (as described above in cancer, ALS, and frontotemporal dementia, having those basic amino acid keys is a favorite means of entry for viral particles into the nucleus (16). 

Nuclear proteins - particularly nuclear envelope proteins communicate with the DNA and RNA in the nucleus. Thus, they have a critical role in maintaining communication with the genetic processes in the cell.


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membranes, nucleus, proteins

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