intracellular membrane transport
Friday 2 June 2006
The compartmentalization of functions into distinct membrane-bound organelles is a central characteristic of cells. The protein and lipid composition of these organelles is unique, a factor that is vital for their proper function.
This necessitates tightly controlled transport of biomolecules from their sites of synthesis or uptake to specific destinations, and mechanisms that prevent promiscuous interactions between cellular membranes that would lead to deleterious mixing of organelle constituents.
One of the major processes responsible for the correct localization of molecules within the cell is called membrane or vesicular transport. In this process, membranous carrier structures bud off a donor compartment and fuse with a recipient one, thus delivering their membrane-associated and soluble luminal constituents to the target organelle.
Proteins to be transported within cells contain structural information that guides them to their correct destinations. Proteins with aberrant structures are misdirected and eventually degraded, as manifested in several inherited diseases in humans, such as cystic fibrosis and Marfan syndrome.
The major cellular routes of membrane transport are the biosynthetic pathway responsible for the transport of proteins synthesized in the endoplasmic reticulum to the extracellular space (secretion) or to other cellular-membrane compartments and the endocytic pathway responsible for the uptake of compounds from the extracellular milieu to be used in cellular metabolism.
Most membrane and secretory proteins, as well as many lipids, are synthesized in the endoplasmic reticulum, whose luminal environment is especially suited to facilitate the proper folding of the synthesized proteins and the initial steps of the glycosylation of proteins.
Proteins that are destined to be transported out of the endoplasmic reticulum move on to the Golgi apparatus, where further post-translational modifications occur.
Subsequently, the proteins are sorted according to their destinations: the plasma membrane (e.g., ion channels, adhesion molecules, and various receptors), regulated secretory granules or vesicles (e.g., hormones, enzymes, and neurotransmitters), or organelles of the endocytic pathway (e.g., lysosomal hydrolases).
Extensive sorting of internalized molecules also takes place along the endocytic pathway: selected molecules are returned to the surface of the cell (e.g., recycling receptors), whereas others are transported to late endosomes and lysosomes, where they are internalized and then degraded. The outgoing and incoming pathways communicate through the exchange of material between the Golgi apparatus and the endosomal elements.
In principle, the consecutive steps in the vesicle-mediated exchange of material consist of the same stages irrespective of the particular donor and acceptor membranes.
These stages include the sorting of proteins and lipids, the formation of transport vesicles, movement of the vesicles along cytoskeletal filaments, recognition of the target organelle, and fusion of the vesicles with the acceptor compartment.
Pathways of Intracellular-Membrane Transport.
from the endoplasmic reticulum through the Golgi complex to the cell surface (biosynthetic pathway)
from the external milieu to early endosomes (endocytic pathway)
- recycling back to the surface
- transported to late endosomes and lysosomes
Step 1: Sorting of Proteins to Transport Vesicles at the Donor Membrane.
Transmembrane receptors that bind soluble and membrane-bound ligands can interact with cytosolic complexes of coat protein.
Small guanosine triphosphatases (GTPases) anchored to the cytosolic face of the donor membrane are critical for the assembly of the coat-protein complex.
The lipid composition of the membrane (e.g., the content of acidic phospholipids) also has an important role in the formation of vesicles.
Examples of genetic defects that affect the sorting of proteins to vesicles include inclusion-cell disease (caused by a defective mannose-6-phosphate recognition marker on ligands), combined deficiency of coagulation factors V and VIII (caused by a defective transmembrane lectin-type receptor), and the Hermansky-Pudlak syndrome (caused by a defective subunit of a coat-protein complex).
Step 2: Cytoskeletal Tracks for the Movement of Vesicles
Once a vesicle has budded off, it does not move passively but rather is guided toward the target membrane by the filamentous structures of the cytoskeleton. Proteins that use the energy of ATP to propel the movement of vesicles or organelles along these filaments are called cytoskeletal motor proteins.
In mammalian cells, microtubules and the associated kinesin and dynein motor proteins form the principal apparatus responsible for organizing directional membrane flow.
In addition, elements consisting of actin and spectrin are thought to connect transport vesicles to microtubules.
Furthermore, actin microfilaments, together with myosin motor proteins, form tracks for the short-distance movement of vesicles, such as when a secretory vesicle has been delivered to the cortical region of the cell and is approaching the plasma membrane.
Step 3: Fusion of Transport Vesicles with Target Membranes
The apparatus responsible for the mutual recognition of a transport vesicle and its target membrane (tethering and docking) and the subsequent bilayer fusion have been studied intensively during the past decade.
The initial interaction between vesicles and their target membrane is facilitated by the regulated assembly of oligomeric protein complexes linking the two membranes together.
Although the molecular events taking place during bilayer fusion are not known in detail, highly conserved membrane-anchored proteins are believed to be instrumental.
The mutual recognition of a transport vesicle and its target organelle is controlled by cycles of nucleotide binding and hydrolysis by Rab proteins, small guanosine triphosphatases (GTPases) belonging to the Ras superfamily.
The GTPase cycle and the attachment of Rab proteins to the membrane are in turn modulated by accessory protein factors.
1. Genetic diseases of intracellular-membrane transport
inclusion cell disease (mucolipidosis II)
combined deficiency of coagulation factors V and VIII
Usher syndrome type 1B
X-linked nonspecific mental retardation
Palmer KJ, Stephens DJ. Biogenesis of ER-to-Golgi transport carriers: complex roles of COPII in ER export. Trends Cell Biol. 2004 Feb;14(2):57-61. PMID: #15106609#
Olkkonen VM, Ikonen E. Genetic defects of intracellular-membrane transport. N Engl J Med. 2000 Oct 12;343(15):1095-104. PMID: #11027745#