The Coat Protein Complex II, or COPII, is a group of

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s that facilitate the formation of

vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...

s to transport proteins from the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

to the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...

or endoplasmic-reticulum–Golgi intermediate compartment. This process is termed

anterograde transport Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytopla ...

, in contrast to the

retrograde transport Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytoplas ...

associated with the

COPI COPI is a coatomer, a protein complex that coats vesicles transporting proteins from the ''cis'' end of the Golgi complex The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most ...

complex. COPII is assembled in two parts: first an inner layer of Sar1, Sec23, and Sec24 forms; then the inner coat is surrounded by an outer lattice of Sec13 and Sec31.

Function

The COPII coat is responsible for the formation of vesicles from the endoplasmic reticulum (ER). These vesicles transport cargo proteins to the Golgi apparatus (in yeast) or the endoplasmic-reticulum-Golgi intermediate compartment (ERGIC, in mammals). Coat assembly is initiated when the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

Ras GTPase Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals ...

Sar1 is activated by its

guanine nucleotide exchange factor Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structu ...

Sec12. Activated Sar1-GTP inserts itself into the ER membrane, binding preferentially to areas of membrane curvature. As Sar1-GTP inserts into the membrane, it recruits Sec23 and Sec24 to make up the inner cage. Once the inner coat is assembled, the outer coat proteins Sec13 and Sec31 are recruited to the budding vesicle. Hydrolysis of the Sar1 GTP to GDP promotes disassembly of the coat. Some proteins are found to be responsible for selectively packaging cargos into COPII vesicles. More recent research suggests the Sec23/Sec24-Sar1 complex participates in cargo selection. For example, Erv29p in ''Saccharomyces cerevisiae'' is found to be necessary for packaging glycosylated pro-α-factor. Sec24 proteins recognize various cargo proteins, packaging them into the budding vesicles.

Structure

The COPII coat consists of an inner layer – a flexible meshwork of Sar1, Sec23, and Sec24 – and an outer layer made of Sec13 and Sec31. Sar1 resembles other Ras-family GTPases, with a core of six

beta strand The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

s flanked by three

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

, and two flexible "switch domains". Unlike other Ras GTPases, Sar1 inserts into membranes via an N-terminal helix (rather than

myristoylation Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminus, N-terminal glycine residue. Myristic acid is a 14-carbon saturat ...

prenylation Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...

). These coat proteins are necessary but insufficient to direct or dock the vesicle to the correct target membrane.

SNARE SNARE proteins – " SNAP REceptor" – are a large protein family consisting of at least 24 members in yeasts, more than 60 members in mammalian cells, and some numbers in plants. The primary role of SNARE proteins is to mediate vesicle fu ...

, cargo, and other proteins are also needed for these processes to occur. Pre-budding complex (composed of Sar1-GTP and Sec23/24) recruits the flexible Sec13p/31p complex, characterized by polymerization of the Sec13/31 complex with other Sec13/31 complexes to form a

cuboctahedron A cuboctahedron is a polyhedron with 8 triangular faces and 6 square faces. A cuboctahedron has 12 identical vertices, with 2 triangles and 2 squares meeting at each, and 24 identical edges, each separating a triangle from a square. As such, it ...

with a broader lattice than its

Clathrin 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 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. Whe ...

vesicle analog. The formation of the cuboctahedron deforms the ER membrane and detaches the COPII vesicle (alongside cargo proteins and v-SNAREs), completing the COPII vesicle budding process.

Regulation

The signal(s) that triggers Sec12 to initiate COPII assembly remains unclear, though some regulators of coat formation are now known. The frequency of COPII formation is regulated in part by Sec16A and Tango1 proteins, likely by concentrating Sec12 in a given location, so it can more efficiently activate Sar1.

Evolution

In mammals there are two Sar1 genes: Sar1A and Sar1B. In cultured mammalian cells the two Sar1 genes appear redundant; however, in animals Sar1B is uniquely required for the formation of large (over 1

micrometer Micrometer can mean: * Micrometer (device), used for accurate measurements by means of a calibrated screw * American spelling of micrometre The micrometre ( international spelling as used by the International Bureau of Weights and Measures; ...

across) COPII-coated vesicles. Similarly, mammals express two Sec23 genes, Sec23A and Sec23B. The two Sec23 isoforms have identical function but are expressed in different body tissues. Both Sec23 proteins can interact with any of the four Sec24 proteins: Sec24A, Sec24B, Sec24C, and Sec24D.

Role in disease

Lethal or pathogenic variants of most COPII proteins have been described. Loss of Sar1B in mice results in death soon after birth. In humans, inheriting two copies of certain SAR1B variants results in

Chylomicron retention disease Chylomicron retention disease is a disorder of fat absorption. It is associated with SAR1B. Mutations in SAR1B prevent the release of chylomicrons in the circulation which leads to nutritional and developmental problems. It is a rare autosomal re ...

, and loss of Sar1B causes a combination of chylomicron retention disease and the neuromuscular disorder

Marinesco–Sjögren syndrome Marinesco–Sjögren syndrome (MSS), sometimes spelled Marinescu–Sjögren syndrome, is a rare autosomal recessive disorder. Presentation The syndrome causes cerebellar ataxia (balance and coordination problems), intellectual disability, congenit ...

. Loss of Sec23A is lethal to mice ''in utero''. In humans, a Sec23A variant causes

Cranio-lenticulo-sutural dysplasia Cranio-lenticulo-sutural dysplasia (CLSD, or Boyadjiev–Jabs syndrome) is a neonatal/infancy disease caused by a disorder in the 14th chromosome. It is an autosomal recessive disorder, meaning that both recessive genes must be inherited from eac ...

, while Sec23B variants are associated with the bone marrow disease

congenital dyserythropoietic anemia type II Congenital dyserythropoietic anemia type II (CDA II), or hereditary erythroblastic multinuclearity with positive acidified serum lysis test (HEMPAS) is a rare genetic anemia in humans characterized by hereditary erythroblastic multinuclearity with ...

and some

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

s. Mice without Sec23B die soon after birth.

Halperin-Birk syndrome Halperin-Birk syndrome (HLBKS) is a rare autosomal recessive neurodevelopmental disorder caused by a null mutation in the ''SEC31A'' gene. Signs and symptoms include intrauterine growth retardation, marked developmental delay, spastic quadriplegi ...

(HLBKS), a rare autosomal recessive neurodevelopmental disorder, is caused by a null mutation in the SEC31A.

Conformational changes

CopII has three specific binding sites that can each be complexed. The adjacent picture (Sed5) uses the Sec22 t-SNARE complex to bind. This site is more strongly bound, and therefore is more favored. (Embo)

Research

Mutations the

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...

at position 39 to asparagine generates a

dominant negative In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

Sar1A bound permanently to GDP; mutating histidine 79 to glycine generates a constitutively active Sar1A, with GTP hydrolysis slowed dramatically.

References

{{DEFAULTSORT:Copii Cell biology