Zip It: How Cells Repair Leaking Membranes
Membrane repair would have been necessary with the first cell. If by a most fantastic miracle scenario — against all probability — a protocell emerged from the primordial soup, it would be all over quickly if the membrane sprang a leak.
Origin-of-life theorists often assume that membranes would spontaneously form naturally around protocells by the properties of lipid self-organization. That, however, is only the beginning of their challenges. Membranes need channels for active transport to control what goes in and out. They also need repair mechanisms if they break. If by inconceivable chance miracles those properties also emerged along with the lucky contents for life inside the membrane, they would never be inherited if they were not preserved in the genetic code. But even that is not enough. Along with code, machinery must be present to translate the code into other machines that know what to do when a membrane breaks. Unwatched membranes are vulnerable to leaks, and they don’t care. Without foresight and oversight, protocells would be like bubbles that pop in due time. Too bad for those hard-won living ingredients inside.
Fixing a Hole
A paper in the EMBO Journal by Yan Zhen et al., “Sealing holes in cellular membranes,” describes how cells actively monitor and repair leaks. The four authors identify multiple mechanisms for membrane repair. The resemblance to Michael Behe’s irreducibly complex blood clotting cascade (Darwin’s Black Box, Chapter 4) is uncanny, yet this is a leak-patching system an order of magnitude smaller!
The bilayered membranes of eukaryotic cells are vital to their very existence, with the plasma membrane separating the cells from their surroundings, and the endomembranes enclosing the various organelles. It is crucial that these membranes are intact so that only gated transport of molecules and ions across them can occur. Defective membrane sealing is indeed associated with a large number of diseases, including myopathies, central and peripheral neurological disorders, and coronary diseases (Cooper & McNeil, 2015). Sealing of holes in membranes is therefore of great importance in biology, both during biogenesis of double‐membrane organelles and as response to membrane damage…. The molecular and cellular mechanisms that have evolved to seal such holes will be discussed in this review. [Emphasis added.]
Ah, yes, they “have evolved.” It was so simple. A chance miracle here, another one there; what’s the issue? And yet the diagrams and descriptions of actual mechanisms for maintaining membrane integrity are mind-boggling in their efficiency and complexity.
Membrane sealing is an ongoing issue for a cell. The authors state that 20-30 percent of muscle cells and 6 percent of skin cells present transient leaks in their membranes that must be sealed promptly, or else serious diseases can occur.
Self-Sealing and Vesicles
For a hole only a few nanometers in size, the properties of lipid attraction allow for spontaneous sealing. Anything larger requires help, though, because membranes are under tension. A hole can quickly rip a stretched cell apart. The cell has at least three ways to reduce membrane tension, the authors say, allowing spontaneous sealing to proceed. Larger holes can be patched by vesicles, which are small lipid-surrounded sacks. A vesicle from outside can cover the hole and merge its lipids with the plasma membrane. Or the membrane can bud outward to bring the intact portions together. Some scientists think that “fusion causes release of an enzyme that promotes membrane sealing.” Imagine a bandage that could merge with your skin!
The cell must have ways to know that a leak has begun. A rapid influx of Ca2+ ions triggers a “simple yet powerful mechanism for detection of membrane integrity.” This, however, requires the presence of proteins that bind to the calcium ions so that they can trigger mechanisms that “promote membrane sealing by membrane fusion, fission or tension reduction.”
What happens to the vesicles after repair has been accomplished? Outside the cell, macrophages can engulf them. Inside, lysomes (the cell’s trash collectors) can engulf them.
Even though membrane repair has mostly been described as a cell autonomous mechanism, muscle cells, which are particularly prone to damage of their plasma membrane, can also engage neighbouring macrophages to pinch off damaged portions of the muscle cell plasma membrane (Middel et al, 2016) (Fig 1F). How macrophage‐mediated removal of the damaged plasma membrane can proceed in a way that preserves membrane integrity still remains to be resolved.
Table 1 in the paper lists at least 16 proteins and protein families that promote membrane sealing in four categories of damage. Annexins, for instance, gather at the site of damage and “assemble into multimeric structures that physically cap the hole in the membrane.” Another protein, named Dysferlin, “Accumulates phosphatidylserine at the site of membrane damage, as an ‘eat‐me’ signal for macrophages.” Dysferlin also “interacts with some annexins” indicating that membrane repair proteins are not superheroes acting alone, but form networks of players that work together. Cooperation between proteins that can solve problems multiplies exponentially the improbability of their spontaneous emergence by unguided natural processes. Here’s another example to show the complexity involved:
Synaptotagmins are integral membrane proteins that function as Ca2+‐sensors that mediate membrane fusion. Among these, Synaptotagmin‐7 (SYT7) has been found to be particularly important for membrane repair. The cytosolic part of SYT7 contains two Ca2+ ‐ and phospholipid‐binding C2 domains that sense cytosolic Ca2+and mediate interactions with membranes. Like other members of the Synaptotagmin family, SYT7 regulates formation of SNARE complexes that drive membrane fusion and thus transduces Ca2+ sensing into membrane fusion ….
The authors go on to describe other proteins that can sense the damage and take appropriate actions. For instance, PDCD6 is a small calcium-binding sensor with big friends.
One of the interacting partners of PDCD6 is ALIX (PDCD6IP), a scaffolding protein involved in diverse cellular functions. ALIX also binds Ca2+, albeit with lower affinity than PDCD6. Injury‐triggered influx of Ca2+ causes accumulation of PDCD6 at the site of injury, and PDCD6 in turn recruits ALIX. ALIX then recruits components of the ESCRT machinery that mediates membrane repair by outward budding and fission of the damaged membrane area….
Not Small Players
Uniprot shows that PDCD6 has 865 amino acids. These are not small players! A whole squadron of machines takes part in healing membrane holes, just like an army of players is required in the blood clotting cascade to repair breaks in blood vessels. There are additional machines involved in repairing internal membranes surrounding organelles and the nucleus. Space forbids discussion here of the ESCRT and SNARE proteins and other players; those interested can read more in the open-access paper or just look at the tables and diagrams to be impressed. But why so many players? The authors refer to backup plans and redundancy:
There is strong evidence that multiple mechanisms have evolved to seal holes in membranes, and there may be good reasons why separate mechanisms exist. Firstly, because membrane integrity is so crucial for cellular viability and functions, the existence of multiple sealing mechanisms could ensure successful sealing even if one mechanism fails. Secondly, the different mechanisms are optimized for sealing of different types of holes …. It is also plausible that additional mechanisms of membrane sealing exist, which have not been characterized yet.
Membrane repair is a key emergency operation for a cell. Just like countries with different military branches for external threats and police agencies for internal threats, cells come well equipped to handle breaches to their security. Saying these systems “have evolved” explains nothing. Something had the foresight to know these systems would be necessary for life and health. Something has the oversight to ensure their successful operation. The irreducible complexity touched on with this brief look at membrane repair provides additional and powerful evidence for intelligent design.