Clathrin is a protein that plays a major role in the formation of coated
vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It
forms a triskelion shape composed of three clathrin heavy chains and three
light chains. When the triskelia interact they form a polyhedral lattice
that surrounds the vesicle. This is how clathrin gets its name, from the Latin
clatratus meaning like a lattice. Coat-proteins, like clathrin, are used
to build small vesicles in order to transport molecules within cells. The
endocytosis and exocytosis of vesicles allows cells to communicate, to transfer
nutrients, to import signaling receptors, to mediate an immune response
after sampling the extracellular world, and to clean up the cell debris left by
tissue inflammation. The endocytic pathway can be hijacked by viruses and
other pathogens in order to gain entry to the cell during infection.
Structure The clathrin triskelion is composed of
three clathrin heavy chains interacting at their C-termini, each ~190 kDa heavy
chain has a ~25kDa light chain tightly bound to it. The three heavy chains
provide the structural backbone of the clathrin lattice, and the three light
chains are thought to regulate the formation and disassembly of a clathrin
lattice. There are two forms of clathrin light chains, designated a and b. The
main clathrin heavy chain, located on chromosome 17 in humans, is found in all
cells. A second clathrin heavy chain gene, on chromosome 22, is expressed in
muscle. Clathrin heavy chain is often described
as a leg, with subdomains, representing the foot, followed by the ankle, distal
leg, knee, proximal leg, and trimerization domains. The N-terminal
domain consists of a seven-bladed β-propeller structure. The other domains
form a super-helix of short alpha helices. This was originally determined
from the structure of the proximal leg domain that identified and is composed
of a smaller structural module referred to as clathrin heavy chain repeat
motifs. The light chains bind primarily to the proximal leg portion of the heavy
chain with some interaction near the trimerization domain. The β-propeller at
the 'foot' of clathrin contains multiple binding sites for interaction with other
proteins. When triskelia assemble together in
solution, they can interact with enough flexibility to form 6-sided rings that
yield a flat lattice, or 5-sided rings that are necessary for curved lattice
formation. When many triskelions connect, they can form a basket-like
structure. The structure shown, is built of 36 triskelia, one of which is shown
in blue. Another common assembly is a truncated icosahedron. To enclose a
vesicle, at least 12 pentagons must be present in the lattice.
In a cell, clathrin triskelion in the cytoplasm binds to an adaptor protein
that has bound membrane, linking one of its three feet to the membrane at a
time. Clathrin cannot bind to membrane or cargo directly and instead uses
adaptor proteins to do this. This triskelion will bind to other
membrane-attached triskelia to form a rounded lattice of hexagons and
pentagons, reminiscent of the panels on a soccer ball, that pulls the membrane
into a bud. By constructing different combinations of 5-sided and 6-sided
rings, vesicles of different sizes may assemble. The smallest clathrin cage
commonly imaged, called a mini-coat, has 12 pentagons and only two hexagons. Even
smaller cages with zero hexagons probably do not form from the native
protein, because the feet of the triskelia are too bulky.
Function Like many proteins, clathrin represents
a perfect case of form following function; it performs critical roles in
shaping rounded vesicles in the cytoplasm for intracellular trafficking.
Clathrin-coated vesicles selectively sort cargo at the cell membrane,
trans-Golgi network, and endosomal compartments for multiple membrane
traffic pathways. After a vesicle buds into the cytoplasm, the coat rapidly
disassembles, allowing the clathrin to recycle while the vesicle gets
transported to a variety of locations. Adaptor molecules are responsible for
self-assembly and recruitment. Two examples of adaptor proteins are AP180
and epsin. AP180 is used in synaptic vesicle formation. It recruits clathrin
to membranes and also promotes its polymerization. Epsin also recruits
clathrin to membranes and promotes its polymerization, and can help deform the
membrane, and thus clathrin-coated vesicles can bud. In a cell, a
triskelion floating in the cytoplasm binds to an adaptor protein, linking one
of its feet to the membrane at a time. The skelion will bind to other ones
attached to the membrane to form a polyhedral lattice, skelion, which pulls
the membrane into a bud. The skelion does not bind directly to the membrane,
but binds to the adaptor proteins that recognize the molecules on the membrane
surface. Clathrin has another function aside from
the coating of organelles. In non-dividing cells, the formation of
clathrin-coated vesicles occurs continuously. Formation of
clathrin-coated vesicles is shut down in cells undergoing mitosis. During
mitosis, clathrin binds to the spindle apparatus, in complex with two other
proteins: TACC3 and ch-TOG/CKAP5. Clathrin aids in the congression of
chromosomes by stabilizing kinetochore fibers of the mitotic spindle. The
amino-terminal domain of the clathrin heavy chain and the TACC domain of TACC3
make the microtubule binding surface for TACC3clathrin to bind to the mitotic
spindle. The stabilization of kinetochore fibers requires the trimeric
structure of clathrin in order to crosslink microtubules.
Clathrin-mediated endocytosis regulates many cellular physiological processes
such as the internalization of growth factors and receptors, entry of
pathogens, and synaptic transmission. It is believed that cellular invaders use
the nutrient pathway to gain access to a cell's replicating mechanisms. Certain
signalling molecules open the nutrients pathway. Two chemical compounds called
Pitstop 1 and Pitstop 2, selective clathrin inhibitors, can interfere with
the pathogenic activity, and thus protect the cells against invasion.
These two compounds selectively block the endocytic ligand association with
the clathrin terminal domain in vitro. Although the specificity of these
compounds to block clathrin-mediated endocytosis has been questioned.
See also AP180
Cap formation Cell migration
Endocytic cycle Epsin
Synaptic vesicle Adaptin
References Further reading
External links MBInfo - Clathrin Mediated Endocytosis
Eukaryotic Linear Motif resource motif class LIG_Clathr_ClatBox_1
Eukaryotic Linear Motif resource motif class LIG_Clathr_ClatBox_2
Clathrin structure Membrane Dynamics
Clathrin Dynamics ASCB Image & Video Library