Microtubule plus-end/positive-end tracking proteins or +TIPs are a type of microtubule associated protein (MAP) which accumulate at the plus ends of microtubules. +TIPs are arranged in diverse groups which are classified based on their structural components; however, all classifications are distinguished by their specific accumulation at the plus end of microtubules and their ability to maintain interactions between themselves and other +TIPs regardless of type. +TIPs can be either membrane bound or cytoplasmic, depending on the type of +TIPs. Most +TIPs track the ends of extending microtubules in a non-autonomous manner.
+TIPs' localization at the plus end of microtubules is a highly relevant aspect of microtubule regulation. A +TIP may promote microtubule growth by catalyzing the addition of tubulin at the plus end, or it may balance microtubules at the cell cortex. Many mechanisms of regulation are not fully understood.
In mitosis, +TIPs allocate microtubule addition and promote dynamical regulation at mitotic kinetochores. [1] They also contribute to the extension of endoplasmic reticulum tubules at expanding microtubule ends. Furthermore, +TIPs aid in advocating organization of specialized microtubule arrays (an oft-cited example being the discrete arrangement of bipolar microtubule bundles in fission yeast).
In addition to the basic known functions of +TIPs, the proteins are crucial for the linkages between microtubule ends and other cellular structures. +TIPs can bind microtubule ends to the cell cortex by colliding to plasma membrane-associated proteins or in the case of some +TIPs, directly to the actin fiber. Moreover, +TIP complexes in budding yeast are utilized for myosin-based transport of microtubule ends. Microtubule plus-end trafficking proteins engage in microtubule actin crosstalk, such as the CLIP-170 (+TIP) that controls actin polymerization—a necessity in mammalian phagocytosis. [2]
+TIPs have been known for an extravagant accumulation by the centrosomes and other structural organizing centers of cells. This leads to the basic assumption that +TIPs may aid in microtubule nucleation and anchoring; however, its distinct role at centrosomes still awaits evidential findings. Overall, +TIPs play a critical part in morphogenesis, cell division, and motility.
About 20 different families of microtubule plus-end trafficking proteins (+TIPs) have been discovered since the first finding of +TIP CLIP-170 (CLIP1) in 1999. Since then +TIPs have been studied thoroughly and still are. The largest group of +TIPs contain complex and large proteins which have low-complexity sequence areas which are affluent in standard proline and serine residues. These type of proteins share a structural basic Ser-X-lle-Pro (where X can be any amino acid). This certain “code” allows these specific complex proteins to be recognizable to another family of +TIPs, known as the EB proteins. The end-binding proteins (EB proteins), have a precise N-terminal domain which is accountable for microtubule binding. The C-terminus however, sustains an alpha-helical coiled region which regulates parallel dimerization of EB monomers and comprises an acidic tail (attaining EEY/F motif) along with an EB homology domain (EBH). The EBH domain and or the EEY/F motif allow the EB proteins to physically interrelate with an array of +TIP in order to recruit them to microtubule ends. [3]
Other classes of +TIPs include the cytoskeleton-associated proteins which are known for their glycine rich domain and a special conserved hydrophobic cavity which permits them to confer interactions with microtubules and EB proteins. There is also a class of +TIPs which substantiates a TOG domain. TOG domains mediate tubulin binding and are important for microtubule growth correlated activity. Basically, the brief classification of +TIPs can be made prior to the specific domain and function rudiments of the particular protein; there exist many more +TIPs, but these correspond to the main oriented and highly studied +TIPs.
Scientists continue to further their understanding of certain mechanisms done by +TIPs and the range of different types of these proteins. Understanding of microtubule plus-end trafficking proteins has greatly expanded since the discovery of CLAP1, and surely will continue to expand as predicted by many researchers and cytologists. Currently, +TIPs may play critical roles in more than just the general aspects known; also with other particular cell structures along with the known structures which are the endoplasmic reticulum, F-actin, vesicles, microtubules, kinetochores, cell cortex, and centrosomes.
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 and 15 nm. They are formed by the polymerization of a dimer of two globular proteins, alpha and beta tubulin into protofilaments that can then associate laterally to form a hollow tube, the microtubule. The most common form of a microtubule consists of 13 protofilaments in the tubular arrangement.
In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.
The microtubule-organizing Centre (MTOC) is a structure found in eukaryotic cells from which microtubules emerge. MTOCs have two main functions: the organization of eukaryotic flagella and cilia and the organization of the mitotic and meiotic spindle apparatus, which separate the chromosomes during cell division. The MTOC is a major site of microtubule nucleation and can be visualized in cells by immunohistochemical detection of γ-tubulin. The morphological characteristics of MTOCs vary between the different phyla and kingdoms. In animals, the two most important types of MTOCs are 1) the basal bodies associated with cilia and flagella and 2) the centrosome associated with spindle formation.
Dyneins are a family of cytoskeletal motor proteins that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargos, provides forces and displacements important in mitosis, and drives the beat of eukaryotic cilia and flagella. All of these functions rely on dynein's ability to move towards the minus-end of the microtubules, known as retrograde transport; thus, they are called "minus-end directed motors". In contrast, most kinesin motor proteins move toward the microtubules' plus-end, in what is called anterograde transport.
A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.
In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs are integral to the stability of the cell and its internal structures and the transport of components within the cell.
In biology, a protein filament is a long chain of protein monomers, such as those found in hair, muscle, or in flagella. Protein filaments form together to make the cytoskeleton of the cell. They are often bundled together to provide support, strength, and rigidity to the cell. When the filaments are packed up together, they are able to form three different cellular parts. The three major classes of protein filaments that make up the cytoskeleton include: actin filaments, microtubules and intermediate filaments.
Dynactin subunit 1 is a protein that in humans is encoded by the DCTN1 gene.
Dynactin is a 23 subunit protein complex that acts as a co-factor for the microtubule motor cytoplasmic dynein-1. It is built around a short filament of actin related protein-1 (Arp1).
CAP-GLY domain containing linker protein 1, also known as CLIP1, is a protein which in humans is encoded by the CLIP1 gene.
Microtubule-associated protein RP/EB family member 1 is a protein that in humans is encoded by the MAPRE1 gene.
Microtubule-associated protein RP/EB family member 2 is a protein that in humans is encoded by the MAPRE2 gene.
Cytoplasmic linker associated protein 2, also known as CLASP2, is a protein which in humans is encoded by the CLASP2 gene.
Cytoskeleton-associated protein 5 is a microtubule-associated protein that in humans is encoded by the CKAP5 gene. It is the homolog of the Xenopus protein XMAP215 and is also known as ch-Tog.
Microtubule-associated protein RP/EB family member 3 is a protein that in humans is encoded by the MAPRE3 gene.
An aster is a cellular structure shaped like a star, consisting of a centrosome and its associated microtubules during the early stages of mitosis in an animal cell. Asters do not form during mitosis in plants. Astral rays, composed of microtubules, radiate from the centrosphere and look like a cloud. Astral rays are one variant of microtubule which comes out of the centrosome; others include kinetochore microtubules and polar microtubules.
The XMAP215/Dis1 family is a highly conserved group of microtubule-associated proteins (MAPs) in eukaryotic organisms. These proteins are unique MAPs because they primarily interact with the growing-end (plus-end) of microtubules. This special property classifies this protein family as plus-end tracking proteins (+TIPs).
In molecular biology, DCTN6 is that subunit of the dynactin protein complex that is encoded by the p27 gene. Dynactin is the essential component for microtubule-based cytoplasmic dynein motor activity in intracellular transport of a variety of cargoes and organelles.
Intracellular transport is the movement of vesicles and substances within a cell. Intracellular transport is required for maintaining homeostasis within the cell by responding to physiological signals. Proteins synthesized in the cytosol are distributed to their respective organelles, according to their specific amino acid’s sorting sequence. Eukaryotic cells transport packets of components to particular intracellular locations by attaching them to molecular motors that haul them along microtubules and actin filaments. Since intracellular transport heavily relies on microtubules for movement, the components of the cytoskeleton play a vital role in trafficking vesicles between organelles and the plasma membrane by providing mechanical support. Through this pathway, it is possible to facilitate the movement of essential molecules such as membrane‐bounded vesicles and organelles, mRNA, and chromosomes.
Neurotubules are microtubules found in neurons in nervous tissues. Along with neurofilaments and microfilaments, they form the cytoskeleton of neurons. Neurotubules are undivided hollow cylinders that are made up of tubulin protein polymers and arrays parallel to the plasma membrane in neurons. Neurotubules have an outer diameter of about 23 nm and an inner diameter, also known as the central core, of about 12 nm. The wall of the neurotubules is about 5 nm in width. There is a non-opaque clear zone surrounding the neurotubule and it is about 40 nm in diameter. Like microtubules, neurotubules are greatly dynamic and the length of them can be adjusted by polymerization and depolymerization of tubulin.