TRAPP (TRAnsport Protein Particle) is a

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 ...

involved in particle transport between

organelle In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...

Protein folding and the Endoplasmic Reticulum (ER)

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 are destined for the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

or export to the extracellular environment in

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

cells are translated on

ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...

s that sit on the

rough 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 ( ...

(RER). Most proteins are co-translationally transported into the ER (i.e., while the ribosome is translating the

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

code into a

polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

, the polypeptide is simultaneously inserted via the

translocon The translocon (also known as a translocator or translocation channel) is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transport ...

pore into the ER). The ER provides an environment that helps nascent polypeptides fold into and become functional or partially functional proteins. The ER provides an

oxidizing Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

environment (for formation of disulfide bonds) and the necessary chaperones (folding assisting agents that are not part of the final protein). Numerous exported proteins form

disulfide bonds In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

—

covalent bonds A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...

that stabilize the protein structure in harsh extracellular environments. A classic example are the disulfide-linked heavy and light chain polypeptides of

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

secreted by

B-cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...

s of the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

. Another key event that takes place in the ER is

N-linked glycosylation ''N''-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), ...

. In this process, polypeptides that have a unique stretch of 3 amino acids (asparagine - X - serine/threonine, where X represents any

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

except

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

) are modified with a complex sugar moiety on the amide group of asparagine. Other types of glycosylations include S-linked (via cysteine residues), C-linked (via tryptophan) and O-linked (via serine or threonine). By far, N-linked glycosylation is the most abundant

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...

found in eukaryotic cells.

Protein export from the ER and the COP II coat

Once proteins have folded and are ready to be transported out of the ER it is thought that they assemble at specific site within the ER called "ER exit sites". These sites can be transient but are most likely situated in the ER where the ER is close to the next transport compartment, the

vesicular-tubular cluster The vesicular-tubular cluster (VTC), also referred to as the endoplasmic-reticulum–Golgi intermediate compartment (ERGIC), is an organelle in eukaryotic cells. This compartment mediates trafficking between the endoplasmic reticulum (ER) and Go ...

(VTC) (also referred to as the ER-Golgi Intermediate Compartment (ERGIC)). The details of how proteins are concentrated or localized to the exit site is unclear but the actual process of

budding Budding or blastogenesis is a type of asexual reproduction in which a new organism develops from an outgrowth or bud due to cell division at one particular site. For example, the small bulb-like projection coming out from the yeast cell is know ...

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 ...

containing these proteins starts with a protein called Sec12. This protein recruits a small

GTPase 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 pro ...

called

Sar1 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 p ...

. Sar1 can be thought of as a switch which is active when bound to GTP and inactive when it hydrolyses the GTP to

GDP Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is often ...

. This in turn leads to the recruitment of a protein complex, the Sec23/Sec24 and the Sec13/Sec31 complex (also known as the

COPII 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 ...

coat). The protein complexes form a mesh at the ER exit site and through mechanical curvature form a little "blob" that pinches off from the ER with proteins inside. The mesh disassembles off the budded vesicle when Sar1 hydrolyses the GTP to GDP. This activity of Sar1 is enhanced by Sec23/24.

Vesicle transport and tethering

Once the vesicles pinch off from the ER they are transported passively (by

diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...

) or actively (by intracellular motors that run on cytoskeletal tracks). The mode of transport seems to be influenced by distance. Short distances may tend towards passive transport, whereas longer distances tend towards

active transport In cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellul ...

. Once these vesicles reach their destination, they need to be first physically linked with their acceptor compartment (else they may float away). This process is facilitated by "

tether A tether is a cord, fixture, or flexible attachment that characteristically anchors something movable to something fixed; it also maybe used to connect two movable objects, such as an item being towed by its tow. Applications for tethers includ ...

s". Tethers come in two "flavors": long protein(s) with domains called "

coiled-coil A coiled coil is a structural motif in proteins in which 2–7 alpha helix, alpha-helices are coiled together like the strands of a rope. (Protein dimer, Dimers and Protein trimer, trimers are the most common types.) Many coiled coil-type protei ...

," or complexes of many subunits which are for the most part

globular A globular cluster is a spheroidal conglomeration of stars. Globular clusters are bound together by gravity, with a higher concentration of stars towards their centers. They can contain anywhere from tens of thousands to many millions of member ...

. The tether that functions to tether ER derived vesicles to the VTC (or

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 ...

in case of lower eukaryotes), the next compartment in the transport pathway, is the Transport Protein Particle (TRAPP).

TRAPP as a tether

TRAPP also comes in two "flavors", TRAPP I & II. TRAPP I is a multisubunit complex that consists of seven subunits (Bet5, Bet3, Trs20, Trs23, Trs31, Trs33, Trs85). TRAPPII has three additional subunits (Trs65, Trs120 and Trs130) and functions as a tether at latter stages of the transport pathway. TRAPP I binds these ER derived vesicles and brings the vesicle closer to the acceptor membrane. This close juxtapositioning of the two membranes allows the interaction between

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 ...

's (soluble NSF (N-ethylmaleimide sensitive Factor) attachment protein receptor) on both compartments. The interacting SNARE's then pull the membranes close and allow for fusion. A recent reportCai et al.
has shown that the initial interaction between TRAPP and the ER derived vesicle is mediated via the interaction between the TRAPP subunit Bet3 and the COPII coat subunit, Sec23. The conventional view of tethering/fusion assumed that the vesicle coat is shed prior to tethering and fusion but this report argues for a model where the initial tethering step takes place on a coated or partially coated vesicle. The TRAPPI complex minus the subunit Trs85 was recently crystallized as two subcomplexes that were then modelled on EM etch data to reveal a possible crystal structure for the entire complex. A putative ypt/rab binding site was indicated on the crystal structure involving the subunits Trs23 and Bet5. Incidentally, all 5 essential small subunits (Trs31, Trs20, Bet3, Bet5 and Trs23) are required to reconstitute efficient exchange activity on ypt1 in vitro. Therefore, it remains to be seen whether the interface between ypt1 and TRAPPI is only confined to Trs23 and Bet5 and how the other subunit influence exchange activity.

Clinical significance

Mutations in the TRAPP system have been associated with neurological deficits.Van Bergen NJ, Guo Y, Al-Deri N, Lipatova Z, Stanga D, Zhao S, Murtazina R, Gyurkovska V, Pehlivan D, Mitani T, Gezdirici A, Antony J, Collins F, Willis MJH, Coban Akdemir ZH, Liu P, Punetha J, Hunter JV, Jhangiani SN, Fatih JM, Rosenfeld JA, Posey JE, Gibbs RA, Karaca E, Massey S, Ranasinghe TG, Sleiman P, Troedson C, Lupski JR, Sacher M, Segev N, Hakonarson H, Christodoulou J (2019) Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability. Brain

References