Endocytosis

Endocytosis

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Endocytosis is a process by which cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

s absorb molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...

s (such as proteins) by engulfing them. It is used by all cells of the body because most substances important to them are large polar
Chemical polarity
In chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...

 molecules that cannot pass through the hydrophobic plasma or cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

. The process which is the opposite to endocytosis is exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...

.

Endocytosis pathways


Endocytosis pathways could be subdivided into four categories: namely, clathrin-mediated endocytosis, caveolae
Caveolae
In biology, caveolae , which are a special type of lipid raft, are small invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells and adipocytes....

, macropinocytosis, and phagocytosis.
  • Clathrin-mediated endocytosis is mediated by small (approx. 100 nm in diameter) vesicles that have a morphologically characteristic crystalline coat made up of a complex of proteins that are mainly associated with the cytosolic protein clathrin
    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 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...

    . Clathrin-coated vesicles (CCVs) are found in virtually all cells and form domains of the plasma membrane termed clathrin-coated pits. Coated pits can concentrate large extracellular molecules that have different receptors responsible for the receptor-mediated endocytosis of ligands, e.g. low density lipoprotein
    Low density lipoprotein
    Low-density lipoprotein is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of cholesterol within the water-based bloodstream...

    , transferrin
    Transferrin
    Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. In humans, it is encoded by the TF gene.Transferrin is a glycoprotein that binds iron very tightly but reversibly...

    , growth factors, antibodies and many others.

  • Caveolae
    Caveolae
    In biology, caveolae , which are a special type of lipid raft, are small invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells and adipocytes....

    are the most common reported non-clathrin-coated plasma membrane buds, which exist on the surface of many, but not all cell types. They consist of the cholesterol-binding protein caveolin
    Caveolin
    Caveolins are a family of integral membrane proteins which are the principal components of caveolae membranes and involved in receptor-independent endocytosis. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules...

     (Vip21) with a bilayer enriched in cholesterol
    Cholesterol
    Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

     and glycolipids. Caveolae are small (approx. 50 nm in diameter) flask-shape pits in the membrane that resemble the shape of a cave (hence the name caveolae). They can constitute up to a third of the plasma membrane area of the cells of some tissues, being especially abundant in smooth muscle
    Smooth muscle
    Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

    , type I pneumocytes, fibroblasts, adipocytes, and endothelial cells. Uptake of extracellular molecules is also believed to be specifically mediated via receptors in caveolae.

  • Macropinocytosis, which usually occurs from highly ruffled regions of the plasma membrane, is the invagination of the cell membrane to form a pocket, which then pinches off into the cell to form a vesicle (0.5–5 µm in diameter) filled with a large volume of extracellular fluid and molecules within it (equivalent to ~100 CCVs). The filling of the pocket occurs in a non-specific manner. The vesicle then travels into the cytosol
    Cytosol
    The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

     and fuses with other vesicles such as endosomes and lysosomes.

  • Phagocytosis is the process by which cells bind and internalize particulate matter larger than around 0.75 µm in diameter, such as small-sized dust particles, cell debris, micro-organisms and even apoptotic cells, which only occurs in specialized cells. These processes involve the uptake of larger membrane areas than clathrin-mediated endocytosis and caveolae
    Caveolae
    In biology, caveolae , which are a special type of lipid raft, are small invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells and adipocytes....

     pathway.


More recent experiments have suggested that these morphological descriptions of endocytic events may be inadequate, and a more appropriate method of classification may be based upon the clathrin-dependence of particular pathways, with multiple subtypes of clathrin-dependent and clathrin-independent endocytosis. Mechanistic insight into non-phagocytic, clathrin-independent endocytosis has been lacking, but a recent study has shown how Graf1 regulates a highly prevalent clathrin-independent endocytic pathway known as the CLIC/GEEC pathway.

Principal components of endocytic pathway


The endocytic pathway of mammaliac cells consists of distinct membrane compartments that internalize molecules from the plasma membrane and recycle them back to the surface (early endosomes and recycling endosomes) or sort them to degradation (late endosomes and lysosomes). The principal components of endocytic pathway are:
  • Early endosomes are the first station on the endocytic pathway. Early endosomes are often located in the periphery of the cell and receive most of types of vesicles coming from the cell surface. They have a characteristic tubulo-vesicular morphology (vesicles up to 1 µm in diameter with connected tubules of approx. 50 nm diameter) and a mildly acid pH. They are principally sorting organelles where many ligands dissociate from their receptors in the acid pH of the lumen and from which many of the receptors recycle to the cell surface (via tubules). It is also the site of sorting into transcytotic pathway to late components (via vesicular component which can form multivesicular bodies (MVB) or endosomal carrier vesicles (ECVs)).
  • Late endosomes receive internalized material en route to lysosomes, usually from early endosomes in the endocytic pathway, from trans-Golgi network (TGN) in the biosynthetic pathway, and from phagosomes in the phagocytic pathway. Late endosomes often contain many membrane vesicles or membrane lamellae and proteins characteristic of lysosomes, including lysosomal membrane glycoproteins and acid hydrolases. They are acidic (approx. pH 5.5), and are part of the trafficking itinerary of mannose-6-phosphate
    Mannose-6-phosphate
    Mannose-6-phosphate is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase....

     receptors. Late endosomes are thought to mediate a final set of sorting events prior to delivery of material to lysosomes.
  • Lysosomes are the last compartment of the endocytic pathway. They are acidic (approx. pH 4.8) and by EM usually appear as large vacuoles (1-2 µm in diameter) containing electron dense material. They have a high content of lysosomal membrane proteins and active lysosomal hydrolases, but no mannose-6-phosphate
    Mannose-6-phosphate
    Mannose-6-phosphate is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase....

     receptor. They are generally regarded as the principal hydrolytic compartment of the cell.Lysosomes chief function in itself is to break down cellular waste products, fats, carbohydrates, proteins, and other macromolecules into simple compounds. These are then returned to the cytoplasm as new cell-building materials. To accomplish the tasks the lysosomes use some 40 different types of hydrolytic enzymes, all of which are manufactured in the endoplasmic reticulum and modified in the Golgi Apparatus.

Clathrin-mediated endocytosis


The major route for endocytosis in most cells, and the best-understood, is that mediated by the molecule clathrin
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 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...

. This large protein assists in the formation of a coated pit on the inner surface of the plasma membrane of the cell. This pit then buds into the cell to form a coated vesicle in the cytoplasm of the cell. In so doing, it brings into the cell not only a small area of the surface of the cell but also a small volume of fluid from outside the cell.

Coats function to deform the donor membrane to produce a vesicle, and they also function in the selection of the vesicle cargo. Coat complexes have been well characterized so far including: coat protein-I (COP-I), COP-II, and clathrin. Clathrin coats are involved in two crucial transport steps: (i) receptor-mediated and fluid-phase endocytosis from the plasma membrane to early endosome and (ii) transport from the TGN to endosomes. In endocytosis, the clathrin coat is assembled on the cytoplasmic face of the plasma membrane, forming pits that invaginate to pinch off (scission) and become free CCVs. In cultured cells, the assembly of a CCV takes ~ 1min, and several hundred to a thousand or more can form every minute. The main scaffold component of clathrin coat is the 190 kD protein called clathrin heavy chain (CHC) and the 25 kD protein called clathrin light chain (CLC), which form three-legged trimers, called triskelions.

Vesicles selectively concentrate and exclude certain proteins during formation and are not representative of the membrane as a whole. AP2 adaptors
AP2 adaptors
The AP2 adaptor complex is a multimeric protein that works on the plasma membrane to internalize cargo in clathrin-mediated endocytosis. It is a stable complex of four adaptins which give rise to a structure that has a core domain and two appendage domains attached to the core domain by polypeptide...

 are multisubunit complexes that perform this function at the plasma membrane. The best-understood receptors that are found concentrated in coated vesicles of mammalian cells are the LDL receptor
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...

 (which removes LDL from circulating blood), the transferrin receptor (which brings ferric ions bound by transferrin
Transferrin
Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. In humans, it is encoded by the TF gene.Transferrin is a glycoprotein that binds iron very tightly but reversibly...

 into the cell) and certain hormone receptors (such as that for EGF
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...

).

At any one moment, about 25% of the plasma membrane of a fibroblast is made up of coated pits. As a coated pit has a life of about a minute before it buds into the cell, a fibroblast takes up its surface by this route about once every 16 minutes. Coated vesicles formed from the plasma membrane have a diameter of about 36 nm and a lifetime measured in a few seconds. Once the coat has been shed, the remaining vesicle fuses with endosomes and proceeds down the endocytic pathway. The actual budding-in process, whereby a pit is converted to a vesicle, is carried out by clathrin assisted by a set of cytoplasmic proteins, which includes dynamin
Dynamin
Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamins are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with, another compartment, both at the cell surface as well as at the...

 and adaptors such as adaptin
Adaptin
Adaptins are proteins that mediate the formation of vesicles by clathrin-coated pits, through interaction with membrane-bound receptors. There are several types of adaptin, each related to a different group of such receptors....

.

Coated pits and vesicles were first seen in thin sections of tissue in the electron microscope by Matt Lions and Parker George. The importance of them for the clearance of LDL from blood was discovered by R. G Anderson, Michael S. Brown and Joseph L. Goldstein
Joseph L. Goldstein
Joseph L. Goldstein from Kingstree, South Carolina is a Nobel Prize winning biochemist and geneticist, and a pioneer in the study of cholesterol metabolism.-Biography:...

 in 1976. Coated vesicles were first purified by Barbara Pearse
Barbara Pearse
Barbara Pearse is a British biological scientist and Fellow of the Royal Society. She works at the Medical Research Council Laboratory of Molecular Biology in Cambridge, United Kingdom....

, who discovered the clathrin coat molecule.

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