What It Takes to Build a Nuclear Membrane
Evolution News & Views
In the cartoon depictions of cells we often see, the nucleus looks about as complicated as a balloon. It's drawn as a thin membrane bubble surrounding the chromosomes. The balloon pops when the cell divides, then the cell blows new balloons around each daughter cell's DNA. What could be simpler?
Authors in Current Biology give a reality check by describing in detail the structure of the nuclear membrane. It's mind-boggling how sophisticated it is -- and they don't even get into the most mind-boggling part: the nuclear pore complexes that let cargo in and out. (At the risk of redlining the boggle-meter, we'll save that subject for another time.)
In their "Quick Guide to Lamins," Wei Xie and Brian Burke introduce us to the complexities of the critically important proteins that make up the nuclear membrane. First of all, what are lamins?
Lamins are structural proteins of the nuclear envelope that are unique to metazoans. Coelenterates, such as hydra, and the nematode Caenorhabditis elegans contain only a single lamin gene. Drosophila has two lamin genes and mammals have three. The lamin genes encode a repertoire of proteins that is augmented by alternative splicing. [Emphasis added.]
So right off the bat, only multicellular animals have lamin genes and proteins. Lamins are among the numerous new cell products, tissues, and organs that appeared without ancestors at the Cambrian explosion. This is confirmed by a 2012 paper that tries to describe the "Evolution of the lamin protein family":
The lamin/IF protein family seems to be restricted to the metazoans. In general, invertebrate genomes harbor only a single lamin gene encoding a B-type lamin. The archetypal lamin gene structure found in basal metazoans is conserved up to the vertebrate lineage.
This distinction with metazoans is curious, since all eukaryotes have a nucleus. Another 2012 paper claims to have found a "lamin-like" protein in a slime mold, but here in 2016, Xie and Burke make no mention of it, suggesting it isn't commonly thought of as an evolutionary precursor (and it just pushes the question further back: where did the slime mold get it?).
Development
The lamins represent the founding members of the intermediate filament (IF) superfamily, and are classed as type V IF proteins. Like all IF proteins, each of the lamins features a globular aminoterminal head domain followed by a central alpha-helical coiled-coil domain. This terminates in a second globular region that has at its core an immunoglobulin fold. In contrast to cytoplasmic IF proteins, each of the lamins contains a nuclear localization sequence that lies just downstream of the coiled-coil domain and is essential for directing the lamins into the nucleus, where they assemble into the nuclear lamina, a protein meshwork that is intimately associated with the nuclear face of the inner nuclear membrane (INM).
They have a zip-code tag that directs them to the nucleus, where they assemble into a meshwork. The membrane has layers: an inner membrane, an outer membrane, and an inter-membrane space. But that is only the beginning. Since mammal lamins are much more complicated and poorly understood, the authors talk about frog lamins, where scientists have been able to tease out some of the details.
Structure
Lamins "spontaneously assemble" into an "orthogonal network" of half-staggered filaments. At least that's what they do in a petri dish. Undoubtedly the process is more involved in the living cell, because "Numerous nuclear pore complexes are associated with this filament meshwork."
Function
Lamins provide both strength and flexibility to the nuclear membrane, and are responsive to the environment. If your lamins are working, be thankful. Bad things happen when they don't.
Forming a 10-20 nm filamentous layer beneath the INM, the mammalian nuclear lamina provides mechanical strength to the nuclear envelope. The nuclei of fibroblasts deficient in A-type lamins lose their normally smooth and round shape; instead irregularities, often severe, are observed. These irregularities are frequently associated with the appearance of nuclear membrane blebs and transient ruptures of the nuclear envelope (Figure 1). Intriguingly, motile cells and cells growing on rigid substrates upregulate A-type lamin expression. Conversely, cells on deformable substrates have reduced A-type lamin expression. It is likely that these differences represent a mechanism by which cells can adapt to changes in mechanical forces transmitted to the nucleus via the cytoskeleton....
It turns out that lamins are in communication with the cytoplasm and the outside world. And that's not all; they communicate with the inside of the nucleus as well:
In addition to their direct structural supporting functions, lamins associate with a number of other nuclear envelope components, including nuclear pore complexes and LINC (linker of the nucleoskeleton and cytoskeleton) complexes. The latter are composed of SUN domain proteins in the INM and the KASH proteins in the outer nuclear membrane (ONM). These proteins establish transluminal interactions within the perinuclear space, the gap that separates the INM and ONM. Through this interaction, SUN-KASH pairs represent links in a molecular chain that spans both nuclear membranes and physically couples the lamina and other nuclear structures to the cytoskeleton. In this way, LINC complexes may have essential roles in nuclear migration/ positioning and mechanotransduction in both health and disease.
The whole "balloon" that appeared so simple at the beginning is composed of several complexes in three layers, with parts that communicate longitudinally and parts that communicate transversely. All of this communicates with the meshwork outside the nucleus, the cytoskeleton. And besides all that, lamins are important players in what goes on inside the nucleus: so much so, that your lifespan might depend on what these proteins do.
It is clear that perturbations in nuclear lamina structure can strongly influence chromatin organization. This may lead to genome-wide changes in replication and transcription activities. As an example, 3D-SIM has revealed that 50% or more of telomeres are associated with the nuclear lamina. The interplay between telomeres and A-type lamins, in conjunction with lamina-associated polypeptide 2-alpha (LAP2-alpha), is thought to regulate cell proliferation and longevity.
Speaking of longevity, there's a strange and highly upsetting genetic disease called progeria. It turns kids old before their time; often they die of "old age" in their teens. That is an example of a laminopathy, one of two dozen lamin disorders that cause severe disability or death. A single point mutation in one lamin gene can cause progeria. Others cause muscular dystrophy or nerve damage, if the individual even survives to birth.
Final Thoughts
We've taken a brief look at proteins that appeared abruptly in the animal kingdom and remain highly conserved throughout life. Their amino acid sequences cannot tolerate mutations. They perform vital functions, both structurally and in interaction with other complexes. They have important roles in cell division and longevity. And these authors did not even get into the fantastic operation at mitosis, when this highly integrated membrane is systematically torn down and rebuilt in the two daughter cells in a matter of minutes.
In other words, one solution to simplistic speculation about evolution is to look closely at a particular phenomenon, with all its intricacies. The design is in the details.
Evolution News & Views
In the cartoon depictions of cells we often see, the nucleus looks about as complicated as a balloon. It's drawn as a thin membrane bubble surrounding the chromosomes. The balloon pops when the cell divides, then the cell blows new balloons around each daughter cell's DNA. What could be simpler?
Authors in Current Biology give a reality check by describing in detail the structure of the nuclear membrane. It's mind-boggling how sophisticated it is -- and they don't even get into the most mind-boggling part: the nuclear pore complexes that let cargo in and out. (At the risk of redlining the boggle-meter, we'll save that subject for another time.)
In their "Quick Guide to Lamins," Wei Xie and Brian Burke introduce us to the complexities of the critically important proteins that make up the nuclear membrane. First of all, what are lamins?
Lamins are structural proteins of the nuclear envelope that are unique to metazoans. Coelenterates, such as hydra, and the nematode Caenorhabditis elegans contain only a single lamin gene. Drosophila has two lamin genes and mammals have three. The lamin genes encode a repertoire of proteins that is augmented by alternative splicing. [Emphasis added.]
So right off the bat, only multicellular animals have lamin genes and proteins. Lamins are among the numerous new cell products, tissues, and organs that appeared without ancestors at the Cambrian explosion. This is confirmed by a 2012 paper that tries to describe the "Evolution of the lamin protein family":
The lamin/IF protein family seems to be restricted to the metazoans. In general, invertebrate genomes harbor only a single lamin gene encoding a B-type lamin. The archetypal lamin gene structure found in basal metazoans is conserved up to the vertebrate lineage.
This distinction with metazoans is curious, since all eukaryotes have a nucleus. Another 2012 paper claims to have found a "lamin-like" protein in a slime mold, but here in 2016, Xie and Burke make no mention of it, suggesting it isn't commonly thought of as an evolutionary precursor (and it just pushes the question further back: where did the slime mold get it?).
Development
The lamins represent the founding members of the intermediate filament (IF) superfamily, and are classed as type V IF proteins. Like all IF proteins, each of the lamins features a globular aminoterminal head domain followed by a central alpha-helical coiled-coil domain. This terminates in a second globular region that has at its core an immunoglobulin fold. In contrast to cytoplasmic IF proteins, each of the lamins contains a nuclear localization sequence that lies just downstream of the coiled-coil domain and is essential for directing the lamins into the nucleus, where they assemble into the nuclear lamina, a protein meshwork that is intimately associated with the nuclear face of the inner nuclear membrane (INM).
They have a zip-code tag that directs them to the nucleus, where they assemble into a meshwork. The membrane has layers: an inner membrane, an outer membrane, and an inter-membrane space. But that is only the beginning. Since mammal lamins are much more complicated and poorly understood, the authors talk about frog lamins, where scientists have been able to tease out some of the details.
Structure
Lamins "spontaneously assemble" into an "orthogonal network" of half-staggered filaments. At least that's what they do in a petri dish. Undoubtedly the process is more involved in the living cell, because "Numerous nuclear pore complexes are associated with this filament meshwork."
Function
Lamins provide both strength and flexibility to the nuclear membrane, and are responsive to the environment. If your lamins are working, be thankful. Bad things happen when they don't.
Forming a 10-20 nm filamentous layer beneath the INM, the mammalian nuclear lamina provides mechanical strength to the nuclear envelope. The nuclei of fibroblasts deficient in A-type lamins lose their normally smooth and round shape; instead irregularities, often severe, are observed. These irregularities are frequently associated with the appearance of nuclear membrane blebs and transient ruptures of the nuclear envelope (Figure 1). Intriguingly, motile cells and cells growing on rigid substrates upregulate A-type lamin expression. Conversely, cells on deformable substrates have reduced A-type lamin expression. It is likely that these differences represent a mechanism by which cells can adapt to changes in mechanical forces transmitted to the nucleus via the cytoskeleton....
It turns out that lamins are in communication with the cytoplasm and the outside world. And that's not all; they communicate with the inside of the nucleus as well:
In addition to their direct structural supporting functions, lamins associate with a number of other nuclear envelope components, including nuclear pore complexes and LINC (linker of the nucleoskeleton and cytoskeleton) complexes. The latter are composed of SUN domain proteins in the INM and the KASH proteins in the outer nuclear membrane (ONM). These proteins establish transluminal interactions within the perinuclear space, the gap that separates the INM and ONM. Through this interaction, SUN-KASH pairs represent links in a molecular chain that spans both nuclear membranes and physically couples the lamina and other nuclear structures to the cytoskeleton. In this way, LINC complexes may have essential roles in nuclear migration/ positioning and mechanotransduction in both health and disease.
The whole "balloon" that appeared so simple at the beginning is composed of several complexes in three layers, with parts that communicate longitudinally and parts that communicate transversely. All of this communicates with the meshwork outside the nucleus, the cytoskeleton. And besides all that, lamins are important players in what goes on inside the nucleus: so much so, that your lifespan might depend on what these proteins do.
It is clear that perturbations in nuclear lamina structure can strongly influence chromatin organization. This may lead to genome-wide changes in replication and transcription activities. As an example, 3D-SIM has revealed that 50% or more of telomeres are associated with the nuclear lamina. The interplay between telomeres and A-type lamins, in conjunction with lamina-associated polypeptide 2-alpha (LAP2-alpha), is thought to regulate cell proliferation and longevity.
Speaking of longevity, there's a strange and highly upsetting genetic disease called progeria. It turns kids old before their time; often they die of "old age" in their teens. That is an example of a laminopathy, one of two dozen lamin disorders that cause severe disability or death. A single point mutation in one lamin gene can cause progeria. Others cause muscular dystrophy or nerve damage, if the individual even survives to birth.
Final Thoughts
We've taken a brief look at proteins that appeared abruptly in the animal kingdom and remain highly conserved throughout life. Their amino acid sequences cannot tolerate mutations. They perform vital functions, both structurally and in interaction with other complexes. They have important roles in cell division and longevity. And these authors did not even get into the fantastic operation at mitosis, when this highly integrated membrane is systematically torn down and rebuilt in the two daughter cells in a matter of minutes.
In other words, one solution to simplistic speculation about evolution is to look closely at a particular phenomenon, with all its intricacies. The design is in the details.
