Three reasons nuclear envelope proteins glide into the nucleus effortlessly

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. 

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).

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 (Uniprot.com and 9). 

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).

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.