Mannose 6-phosphate receptor
Encyclopedia
In the fields of biochemistry
and cell biology
, mannose 6-phosphate receptors (MPRs) are protein
s that bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver them to pre-lysosomal compartments. There are two different MPRs, one of ~300kDa and a smaller, dimeric receptor of ~46kDa. The larger receptor is known as the cation-independent mannose 6-phosphate receptor (CI-MPR
), while the smaller receptor (CD-MPR
) requires divalent cations to efficiently recognize lysosomal hydrolases. While divalent cations are not essential for ligand binding by the human CD-MPR, the nomenclature has been retained.
Both of these receptors bind terminal mannose 6-phosphate with similar affinity (CI-MPR = 7 μM, CD-MPR = 8 μM) and have similar signals in their cytoplasmic domains for intracellular trafficking.
and encounter MPRs at the TGN
.
At the TGN, MPR-ligand complexes interact with the heterotetrameric complex of the AP1 clathrin adaptor complex and/or members of the GGA
family of clathrin adapters. Binding concentrates receptor-ligand complexes into tubular structures at the TGN and they are packaged into clathrin-coated vesicles
. These vesicles are very dynamic and live-cell video microscopy shows that they fuse with early endosomes that are positive for internalized transferrin. MPRs are then segregated from transferrin within early endosomes, yielding two distinct domains.
s use such a pathway while TGN46
recycles back to the Golgi via recycling endosomes. However, MPRs bind their ligands in a pH
dependent manner and need a pH < 6 to dissociate the ligand from the MPR. The pH of the early endosome has been measured to be between pH 6.2-6.3, while the pH of the late endosome is pH 5.2-5.8; this was measured using the intensity ratio of fluorescein
. RAB9A
is a late endosomal Rab protein that is absolutely required for MPR retrieval. In addition, Press et al. (1998) showed that the late endosome Rab7 was required for proper MPR trafficking. When they expressed inactive Rab7 in cells, the MPR was trapped in an early endosomes and could not return to the TGN . More recent work has also confirmed the role that Rab7 plays in proper retromer localization and function. Thus, the MPR must pass through the late endosome to dissociate lysosomal hydrolases before return to the TGN.
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
and cell biology
Cell biology
Cell biology is a scientific discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level...
, mannose 6-phosphate receptors (MPRs) are protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver them to pre-lysosomal compartments. There are two different MPRs, one of ~300kDa and a smaller, dimeric receptor of ~46kDa. The larger receptor is known as the cation-independent mannose 6-phosphate receptor (CI-MPR
Insulin-like growth factor 2 receptor
In the fields of biochemistry and cell biology, the insulin-like growth factor 2 receptor , also called the cation-independent mannose-6-phosphate receptor is a protein that in humans is encoded by the IGF2R gene...
), while the smaller receptor (CD-MPR
Cation-dependent mannose-6-phosphate receptor
In the fields of biochemistry and cell biology, the cation-dependent mannose-6-phosphate receptor also known as the 46 kDa mannose 6-phosphate receptor is a protein that in humans is encoded by the M6PR gene....
) requires divalent cations to efficiently recognize lysosomal hydrolases. While divalent cations are not essential for ligand binding by the human CD-MPR, the nomenclature has been retained.
Both of these receptors bind terminal mannose 6-phosphate with similar affinity (CI-MPR = 7 μM, CD-MPR = 8 μM) and have similar signals in their cytoplasmic domains for intracellular trafficking.
Function
Early in the Golgi, the oligosaccharide chains of lysosomal hydrolases are tagged with terminal phosphomannosyl moieties. The lysosomal hydrolases continue through the GolgiGolgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
and encounter MPRs at the TGN
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
.
At the TGN, MPR-ligand complexes interact with the heterotetrameric complex of the AP1 clathrin adaptor complex and/or members of the GGA
GGA
GGA or Gga may refer to:*Gereja Generasi Apostolik, Apostolic Generation Church in English*Girl Guides Australia*Good girl art*Goemon's Great Adventure, a 1998 Nintendo 64 video game...
family of clathrin adapters. Binding concentrates receptor-ligand complexes into tubular structures at the TGN and they are packaged into clathrin-coated vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
. These vesicles are very dynamic and live-cell video microscopy shows that they fuse with early endosomes that are positive for internalized transferrin. MPRs are then segregated from transferrin within early endosomes, yielding two distinct domains.
Recycling to the trans-Golgi network
The return route taken by MPRs to the TGN has been somewhat controversial. Because depletion of AP1 or so-called retromer proteins results in MPR sequestration in early endosomes, many have concluded that the MPR traffics directly from early endosomes to the TGN. The bacterial shiga toxin and cholera toxinCholera toxin
Cholera toxin is a protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection.- Structure :...
s use such a pathway while TGN46
TGOLN2
Trans-Golgi network integral membrane protein 2 is a protein that in humans is encoded by the TGOLN2 gene.-Further reading:...
recycles back to the Golgi via recycling endosomes. However, MPRs bind their ligands in a pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
dependent manner and need a pH < 6 to dissociate the ligand from the MPR. The pH of the early endosome has been measured to be between pH 6.2-6.3, while the pH of the late endosome is pH 5.2-5.8; this was measured using the intensity ratio of fluorescein
Fluorescein
Fluorescein is a synthetic organic compound available as a dark orange/red powder soluble in water and alcohol. It is widely used as a fluorescent tracer for many applications....
. RAB9A
RAB9A
Ras-related protein Rab-9A is a protein that in humans is encoded by the RAB9A gene.-Interactions:RAB9A has been shown to interact with RABEPK and TIP47.-Further reading:...
is a late endosomal Rab protein that is absolutely required for MPR retrieval. In addition, Press et al. (1998) showed that the late endosome Rab7 was required for proper MPR trafficking. When they expressed inactive Rab7 in cells, the MPR was trapped in an early endosomes and could not return to the TGN . More recent work has also confirmed the role that Rab7 plays in proper retromer localization and function. Thus, the MPR must pass through the late endosome to dissociate lysosomal hydrolases before return to the TGN.