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Scientists Determine Atomic Structure Of Lego-Like Molecule That Self-Assembles Into Cell's Cargo Capsule

May 27, 1999
University Of California, San Francisco
Scientists have determined the atomic structure of the three-spoked molecule called clathrin which "self-assembles," Lego-like, into a protective sphere just inside cell membranes and safely transports nutrients, hormones and other cargo into our cells.

Scientists have determined the atomic structure of thethree-spoked molecule called clathrin which"self-assembles," Lego-like, into a protective sphere justinside cell membranes and safely transports nutrients,hormones and other cargo into our cells.

The versatile molecule, which spontaneously disassembles andrecycles after each delivery, was recently shown by otherresearchers to be targeted by the HIV virus. Invadingviruses dupe clathrin into sequestering the cell's CD4immune molecules, thereby preventing them from launching adefense against the virus.

Knowledge of clathrin's atomic-level structure may enableresearchers to counter the virus's pernicious strategy.

"If you know the structure, you can start understanding howclathrin is regulated," says Frances M. Brodsky, PhD, aleading clathrin researcher and a professor ofbiopharmaceutical sciences, pharmaceutical chemistry andmicrobiology and immunology at the University of CaliforniaSan Francisco (UCSF) where the study was carried out.

Brodsky and colleagues report the research in the May 27issue of the journal Nature.

The atomic structure hints at what one of the UCSFscientists terms a "universal coupling motif" -- aconfiguration possibly shared by all proteins capable ofcoming together, like clathrin, and enclosing vital materielin membranes for safe transit. Such controlled transport isessential for supplying nutrients and vitamins to cells, forsecretion of hormones and for signaling cells to changetheir fate.

"Likely many proteins that contribute to traffic flow willhave this motif," says Robert Fletterick, co-author on theNature paper and a UCSF professor of biochemistry andbiophysics. "Several have already been identified. Theunmistakable footprint of the motif has just shown up in aprotein involved in docking cells that are transported inmembranous vessels in all animals and plants."

At the scale of the entire molecule, clathrin is shapedsomewhat like a flattened tripod, and each three-leggedstructure is termed a triskelion. When precious proteins areto be hauled into the cell, clathrin molecules come togetherby the thousands and spontaneously assemble into a lattice,like a sheet of ice forming when the temperature drops. Theclathrin lattice then folds into a ball.

"If you take a bunch of triskelions, they will self-assembleinto a sphere," Brodsky says simply.

The assembly is triggered when legs of adjacent clathrintriskelions pair up. As the assembly progresses, thetriskelions form a growing network of hexagonal shapes.Ultimately, the flat lattice folds into a sphere made up ofhexagonal shapes near the equator and clathrin pentagonsnear north and south poles, just like a soccerball.

The self-assembly not only assures safe transit fornutrients, hormones and the like, but also preciselyregulates which molecules gain entry into the cell, andwhen: No clathrin, no entry.

When an iron-bearing protein, or insulin or the cholesterolmolecule, for example, seek entry, each normally docks witha receptor protruding from the outer surface of the cell'smembrane and specialized to accept only one kind ofmolecule. If the appropriate receptor -- say the receptorfor insulin -- is not present, entry is barred.

But even when the insulin protein successfully links up withits receptor, the resulting insulin-receptor package mustbe recognized by another specialized cellular protein togain entrance. This protein, known as an adaptor, acts asboth bridge tender and bridge, binding to a specificreceptor-cargo package on the outside the cell, and then tothe clathrin molecule inside the cell membrane.

When triggered by the adaptor, the three-legged clathrinmolecules line up with one another and begin the rapidpolymerization into a lattice. The buildup pulls the adaptorand its receptor-cargo packet into the cell, eventuallyplucking a chunk of the cell's membrane inside, along withthe receptor and its vital cargo. All this material becomesenveloped as the clathrin lattice folds into a sphere.

"The cell has figured out how to regulate the input ofnutrients, hormones and other vital molecules," Brodskysays. "Central to that process is clathrin's capacity tofirst form a cage to transport its cargo, then disassemble,unload the cargo and finally recycle itself. It's aversatile molecule with a structure that determines itsself-assembling and disassembling properties."

The scientists discovered -- and report in Nature -- thatmost of the filamentous molecule is composed of sevenrepeats of five "helical hairpin" units. The helical hairpinis a common protein structure, but the repeating sequence offive may be unique to proteins involved in linking up toform coated vesicles for transport as clathrin does, saysRobert Fletterick.

"The clathrin structure shows a gratifying elegance thatwould have delighted Bucky Fuller," he adds.

The researchers employed an advanced form of x-raycrystallography to determine the atomic structure ofclathrin's active site of polymerization. The experimentmade use of the Advanced Light Source at Lawrence BerkeleyNational Laboratory (LBNL).

Lead author of the paper is Joel A. Ybe, PhD, assistantresearch biochemist in the Brodsky laboratory. Senior authoris Peter K. Hwang, PhD, associate research biochemisty inthe UCSF biochemistry and biophysics department.

Other collaborators and co-authors are Kai Lin, PhD, formerpostdoctoral fellow in Fletterick's laboratory; Shu-Hui Liu,PhD, postdoctoral fellow and Lin Chen, research associate,both in Brodsky's lab. Also, Thomas N. Earnest, PhD, of theMacromolecular Crystallography Facility at LBL's AdvancedLight Source, and Kay Hoffman, PhD, staff scientist at theBioinformatics Group of MEMOREC in Germany.

The research was funded by the National Institutes ofHealth.

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University Of California, San Francisco. "Scientists Determine Atomic Structure Of Lego-Like Molecule That Self-Assembles Into Cell's Cargo Capsule." ScienceDaily. ScienceDaily, 27 May 1999. <>.
University Of California, San Francisco. (1999, May 27). Scientists Determine Atomic Structure Of Lego-Like Molecule That Self-Assembles Into Cell's Cargo Capsule. ScienceDaily. Retrieved February 20, 2017 from
University Of California, San Francisco. "Scientists Determine Atomic Structure Of Lego-Like Molecule That Self-Assembles Into Cell's Cargo Capsule." ScienceDaily. (accessed February 20, 2017).