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Just-in-Time Delivery in Living Cells

During the coronavirus crisis, truckers have played an essential role in getting masks, medicines, and equipment to hospitals that were overwhelmed, and food to the grocery stores to prevent a starvation crisis as people obeyed stay-at-home orders. Some of the truckers drove long all-night shifts to meet the critical demand. Non-essential deliveries of goods from retail merchants like Amazon continued mostly uninterrupted, too. 

Human delivery systems rely on distributed storage. Cells know all about this. A cell is a large place, like a city to the molecules inside; it is inefficient to store needed cargoes far from their work sites. Within the cell, highways of microtubules grow in the directions that cargo carriers like kinesins need them. Some new discoveries show that additional mechanisms supplement those well-known processes to provide just-in-time delivery.

LPL Warehousing

Many health-conscious people monitor their triglycerides, knowing that high levels pose a risk factor for cardiovascular disease. At the cellular level, a protein called LPL (lipoprotein lipase) is there to help regulate triglycerides. Lipases are enzymes necessary for the proper distribution and utilization of lipids in the human body, but some of these enzymes can be dangerous if not handled carefully. LPL, for instance, could hydrolyze useful lipids within the cell if turned loose, instead of going to work in the interstitial space in capillaries where the triglycerides need to be dismantled before they contribute to atherosclerosis.

Scientists publishing in PNAS found “an unexpected twist” in the way cells in the capillaries sequester these enzymes until they are called for: the cell bundles them into helical form and packages them in vesicles. Upon translation in the ribosomes, LPLs in adipocytes are sent to the Golgi apparatus for maturation and proper folding. When ready, they are accompanied by another enzyme, SDC1 (syndecan-1), for sequestration into vesicles. There, a third enzyme named HSPG stabilizes them, rendering them inactive, as two strands of LPL wind into a helical shape. When they get the call for action, they emerge from their vesicles like firefighters at a station, unwind from their helical shape, separate, and hang onto HSPGs on the cell surface. Then, they are moved to the surfaces of capillary endothelium, ready to put out the triglyceride fires. The authors say,

An inactive form of LPL is likely physiologically important for storage during trafficking. LPL has been reported to have a cryptic state in cell lysate that is inactive and concentration-dependent. This cryptic state shares many similarities to the helical LPL that we identified. Cells store pools of LPL that can be released in response to nutritional signaling. However, it is not ideal to have active LPL inside the cell, where it could potentially hydrolyze needed lipids. LPL in an inactive conformation would provide an appealing solution to the issue and give the cell flexibility to store LPL without concern for unwanted hydrolysis (Fig. 8). A helical structure is also a stable way to pack an aggregation-prone protein, such as LPL, for efficient storage in a small compact space.

The authors’ diagram of the helical shape looks very elegant, something like a symmetrical braided tube. It is held together by disulfide bonds and N-linked glycans. 

The Cell’s FedEx System

News from Vanderbilt University announced another delivery mechanism, this time for proteins called retromers. The catchy headline says, “Biology researchers capture shape-shifting delivery structures in body’s cellular ‘FedEx system.’” Amazingly, the retromers are contortionists at their job. 

A new cellular biology study, published last month in the journal Structure by scientists at Vanderbilt, reports a shape-shifting structure in the human body which plays an important role in the timely delivery of fats and proteins. 

Led by Lauren Jackson, assistant professor of biological sciences and biochemistry at Vanderbilt, the work is the first to visualize this structure — a type of protein complex found in human cells known as retromer — and report its unique ability to transfigure itself into a variety of different architectures and structures.

How do they qualify as delivery personnel? They deliver “parcels,” the scientists explain. Their jobs are essential, as seen by what happens when they fail to arrive with the goods.

The human body relies on this parcel delivery process (referred to by Jackson as a “biological FedEx system”) to deliver important protein and fatty lipid molecules to the right places at the right times. In the event of delivery failures or interruptions, cells lose what they need to function and human diseases and neurological disorders such as Alzheimer’s and Parkinson’s can emerge.

Before enterprises such as FedEx, UPS, or the U.S. mail can deliver parcels, they need to sort them. The article describes “sorting stations” in cells called endosomes, where this takes place. The paper’s Abstract says,

Our data suggest the metazoan retromer is an adaptable and plastic scaffold that accommodates interactions with different sorting nexins to sort multiple cargoes from endosomes their final destinations.

The retromers can take on a variety of forms, joining in complexes of “heterotrimers; dimers of trimers; tetramers of trimers; and flat chains.” Imagine getting that ability by chance mutations. Here’s another case where cryo-electron microscope allowed the researchers to watch the show.

“This flexible scaffold structure plays a key role in the sorting and delivery process,” said Jackson. “These structures reveal how one complex alone is able to sort and deliver cellular ‘cargo’ to different destinations.”

Labeling the Trash

It’s not just cargo that needs labeling. Sorting operations must identify trash, too, and recycle what they can. Cellular trash is marked by a molecule called ubiquitin. Cryo-electron microscopy  at the Max Planck Institute reveals how one enzyme controls another enzyme that slaps the ubiquitin “recycle me” label on spent proteins. 

Proteins are molecular work horses in the cell that perform specific tasks, but it is essential that the timing of protein activities is exquisitely controlled. When proteins have fulfilled their tasks, degradation of these proteins will end processes that are unneeded or detrimental. To control timing, a label — called “ubiquitin” — is attached to unwanted proteins, marking the protein for degradation. Although complex molecular machineries were known to attach ubiquitin, how these machines carry out the labeling process was unknown.

The machine that does this is called NEDD8, and it’s always “in the right place, at the right time.” Its job is to switch on other molecules, the E3 ligases, that attach the ubiquitin labels. “We discovered how NEDD8 induces an E3 molecular machine to bring the ubiquitin tag to its targets,” the researchers say.

Just in Time for Sex

A last story about just-in-time delivery is quite interesting, seeing as it helped each of us get born. Scientists at University of California wondered how sperm unpack Dad’s genome so that it can merge with Mom’s at the moment of fertilization. Obviously a package like that requires special handling, but any parcel delivery system faces two issues: the package has to arrive with the train on time, and it has to be capable of being opened. Imagine getting your essential order from Amazon in a box you can’t open, or once opened, is so tangled with packing material you can’t get to the goods! Consider how the male haploid genome arrives:

Sperm can be up to 20 times smaller than a normal cell in the body. And while sperm carry only half as much genetic material as a regular cell, it needs to be folded and packaged in a special way in order to fit. One way nature does this is by replacing histones — proteins around which DNA is wound, like beads on a necklace — with a different type of protein called protamines.

 Thankfully, the fertilized egg knows how to get to the precious genes that helped make you. 

Researchers at University of California San Diego School of Medicine have discovered that the enzyme SPRK1 leads the first step in untangling a sperm’s genome, kicking out special packing proteins, which opens up the paternal DNA and allows for major reorganization — all in a matter of hours.

These stories are among many about just-in-time delivery in living cells. They show intelligent design at work not only in the sequences of building blocks, and the shape of the machineries they build, but also the time element that assures they get to the right place at the right time.

Photo credit: Obi Onyeador via Unsplash.