Coatomer

The coatomer is a protein complex ^[1] that coats membrane-bound transport vesicles. Two types of coatomers are known:

Contents

• Structure
• COP I
• COP II
• Diseases associated with defects in COP
• References

• COPI (retrograde transport from trans-Golgi network to cis-Golgi network and endoplasmic reticulum)
• COPII (anterograde transport from ER to the cis-Golgi)

Coatomers are functionally analogous and evolutionarily homologous to clathrin adaptor proteins, also known as adaptins, ^[2] which regulate endocytosis from the plasma membrane and transport from the trans-Golgi network to lysosomes.

Structure

The coatomer protein complex is made up of seven nonidentical protein subunits. ^[3] These seven nonidentical protein subunits are part of two protein subcomplexes. ^[3] The first subcomplex consists of Ret1(α-COP), Sec27(β’-COP), and Sec 28(ε-COP). ^[3] The second subcomplex consists of Sec26 (β-COP), Sec21 (γ-COP), Ret2(δ-COP), and Ret3 (ζ-COP). ^[3]

COP I

COPI is a coatomer that coats the vesicles transporting proteins from the Golgi complex to the ER. ^[4] This pathway is referred to as retrograde transport. Before the COP I protein can coat vesicles on the Golgi membrane, it must interact with a small GTPase called ARF1 (ADP ribosylation factor). ^[5] ARF1 that is bound to GDP interacts with the golgi complex membrane. ^[5] Next, guanine nucleotide exchange factors (GEFs) in the golgi complex membrane exchange the GDP bound to ARF1 for GTP. ^{[5] [6]} This activates ARF1, allowing it to insert an amphipathic alpha helix into the lipid bilayer of the Golgi complex. ^[6] Next, the ARF1 protein recruits COP1 to the golgi complex membrane by interacting with β-COP and γ-COP. ^[6] Once the vesicle is coated, it begins to travel to the ER. Before the vesicle can fuse with the ER membrane, the coats surrounding the vesicle must dissociate. ARF-GAP1 is responsible for deactivating the ARF1 protein by activating the GTPase. ^[6] When ARF1 switches to its GDP- bound conformation, it causes the COP1 coat to destabilize. ^[6]

The COP1 proteins recognize the proper cargo by interacting with sorting signals on the cytoplasmic domains of the protein. ^[7] The most common sorting signals include the amino acid sequence KKXX or KDEL. ^[7] KKXX signals are associated with transmembrane ER domains and KDEL signals are associated with proteins in the ER lumen. ^[7] COP1 coated vesicles also contain p24 proteins that assist with cargo sorting. ^[8]

COP II

COP II is a coatomer that coats the vesicles transporting proteins from the ER to the golgi complex. ^[4] This pathway is referred to as anterograde transport. ^[4] The first step in the COP II pathway is the recruitment of a small GTPase named Sar1 to the ER membrane. ^[9] Once Sar1 interacts with the ER membrane, a membrane protein called Sec12 acts a guanine nucleotide exchange factor and substitutes GDP for GTP on Sar1. ^[9] This activates the Sar1 protein, causing its amphipathic alpha helix to bind to the ER membrane. ^[9] Membrane bound Sar1 attracts the Sec23-Sec24 protein heterodimer to the ER membrane. Sar1 directly binds to Sec23 while Sec24 directly binds to the cargo receptor located on the ER membrane. ^[10]

The Sar1-GTP and Sec23-24 complex recruits another protein complex called Sec13/Sec31. This complex polymerizes to form the outer layer of the coat. ^[10] COP II vesicles must shed their coat before they can fuse with the cis-Golgi membrane. This occurs when the GTP on Sar1 is hydrolyzed by the GTPase activating protein. ^[10] Activation of the GTPase also reverses the interaction between Sar1 and the Sec23-Sec24 protein dimer. ^[10] COP II vesicles select the proper cargo by directly interacting with ER export signals that are present in transmembrane ER proteins. ^[7] There are several classes of ER export signals that have been identified in various organisms. The involvement of so many different ER export signals means that there are multiple binding sites for the export signals. ^[7]

Diseases associated with defects in COP

Newly made secretory proteins must pass through the ER and the golgi complex before they can leave the cell. Problems with COP II early secretory pathways can lead to a disease called Congenital Dyserythropoietic Anemia type II. ^[11] This is an autosomal recessive disorder that results from the mutation of a gene called Sec23B. ^[11] This gene plays an important role in regulating the transport of proteins within cells. ^[11] Symptoms for Congenital Dyserythropoietic Anemia type II include anemia, jaundice, low reticulocyte count, splenomegaly, and hemochromatosis. ^[12] Congenital Dyserythropoeitic Anemia Type II is normally diagnosed during adolescence or early adulthood. ^[12] Congenital Dyserythropoetic Anemia Type II is a very rare disease with only a few hundred cases worldwide. ^[12] Treatment for the disease involves blood transfusions, iron therapy, and the removal of the spleen. ^[12]

Another disease associated with deficiencies in the COP II pathway is combined factor V and factor VIII deficiency. ^[11] In this disease, the person produces Factor V and VIII but they can not transport factor V or VIII into the bloodstream. ^[11] This is an autosomal recessive disorder that leads to bleeding symptoms, epistaxis, menorrhagia, and excessive bleeding after trauma. ^[13] The disease can be diagnosed after screening tests are analyzed by a specialized healthcare provider. ^[13] The mutation of the MCFD2 gene is what causes combined factor V and VIII deficiency. ^[13] Treatment for the disease includes administrating frozen plasma and desmopressin to the patient. ^[13]

Related Research Articles

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 inside the cell before the vesicles are sent to their destination. It resides at the intersection of the secretory, lysosomal, and endocytic pathways. It is of particular importance in processing proteins for secretion, containing a set of glycosylation enzymes that attach various sugar monomers to proteins as the proteins move through the apparatus.

GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a protein domain common to many GTPases.

The Coat Protein Complex II, or COPII, is a group of proteins that facilitate the formation of vesicles to transport proteins from the endoplasmic reticulum to the Golgi apparatus or endoplasmic-reticulum–Golgi intermediate compartment. This process is termed anterograde transport, in contrast to the retrograde transport associated with the COPI 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.

COPI is a coatomer, a protein complex that coats vesicles transporting proteins from the cis end of the Golgi complex back to the rough endoplasmic reticulum (ER), where they were originally synthesized, and between Golgi compartments. This type of transport is retrograde transport, in contrast to the anterograde transport associated with the COPII protein. The name "COPI" refers to the specific coat protein complex that initiates the budding process on the cis-Golgi membrane. The coat consists of large protein subcomplexes that are made of seven different protein subunits, namely α, β, β', γ, δ, ε and ζ.

Brefeldin A is a lactone antiviral produced by the fungus Penicillium brefeldianum. Brefeldin A inhibits protein transport from the endoplasmic reticulum to the golgi complex indirectly by preventing association of COP-I coat to the Golgi membrane. Brefeldin A was initially isolated with hopes to become an antiviral drug but is now primarily used in research to study protein transport.

TRAPP (TRAnsport Protein Particle) is a protein involved in particle transport between organelles.

ADP ribosylation factors (ARFs) are members of the ARF family of GTP-binding proteins of the Ras superfamily. ARF family proteins are ubiquitous in eukaryotic cells, and six highly conserved members of the family have been identified in mammalian cells. Although ARFs are soluble, they generally associate with membranes because of N-terminus myristoylation. They function as regulators of vesicular traffic and actin remodelling.

Vesicular transport adaptor proteins are proteins involved in forming complexes that function in the trafficking of molecules from one subcellular location to another. These complexes concentrate the correct cargo molecules in vesicles that bud or extrude off of one organelle and travel to another location, where the cargo is delivered. While some of the details of how these adaptor proteins achieve their trafficking specificity has been worked out, there is still much to be learned.

ADP-ribosylation factor 1 is a protein that in humans is encoded by the ARF1 gene.

Coatomer subunit beta is a protein that in humans is encoded by the COPB1 gene.

Coatomer subunit alpha is a protein that in humans is encoded by the COPA gene.

ADP-ribosylation factor GTPase-activating protein 1 is an enzyme that in humans is encoded by the ARFGAP1 gene. Two transcript variants encoding different isoforms have been found for this gene.

Coatomer subunit beta is a protein that is encoded by the COPB2 gene in humans.

Coatomer subunit gamma is a protein that in humans is encoded by the COPG gene. It is one of seven proteins in the COPI coatomer complex that coats vesicles as they bud from the Golgi complex.

ADP-ribosylation factor 4 is a protein that in humans is encoded by the ARF4 gene.

KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum protein retention receptor 1, also known as KDELR1, is a protein which in humans is encoded by the KDELR1 gene.

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 recessive disorder with around 40 cases reported worldwide. Since the disease allele is recessive, parents usually do not show symptoms.

The C-terminal domain ofBeta2-adaptin is a protein domain is involved in cell trafficking by aiding import and export of substances in and out of the cell.

Exomer is a heterotetrameric protein complex similar to COPI and other adaptins. It was first described in the yeast Saccharomyces cerevisiae. Exomer is a cargo adaptor important in transporting molecules from the Golgi apparatus toward the cell membrane. The vesicles it is found on are different from COPI vesicles in that they do not appear to have a "coat" or "scaffold" around them.

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 quadriplegia with profound contractures, dysmorphism, and optic nerve atrophy with no eye fixation. Brain MRI demonstrated microcephaly and agenesis of the corpus callosum.

References