CD91 α2M-R (α2 macroglobulin receptor), LRP1 (low density lipoprotein receptor-related protein 1)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Fibroblast
Neuron
Astrocyte
Epithelial Cell
Muscle, Smooth
Dendritic Cell
Monocyte
Macrophage
Lung
Liver
Kidney
Syncytiotrophoblast
Ovary
Testis
Nervous system
Reticulocyte
Erythroblast
Hepatocyte
Gastrointestine
85 / 85
515 / 515

Expression
CD91 is expressed on the phagocytes of liver, lung and lymphoid tissues, but not on antigen-presenting cells.  It is  expressed on neurons and astrocytes in the central nervous system, epithelial cells of the gastrointestinal tract, smooth muscle cells, fibroblasts, Leydig cells in the testis, granulosa cells in the ovary, dendritic cells of the kidney, hepatocytes, macrophages and syncytiotrophablasts.

Structure
MOLECULAR FAMILY NAME1: Belongs to the low density lipoprotein receptor family.

CD91 is a single-pass type-1 glycoprotein.  CD91 is cleaved into 2 subunits, an α extracellular 515 kDa chain that binds non-covalently to the β transmembrane 85 kDa chain.  The α chain contains 4 clusters of cysteine-rich low density lipoprotein (LDL) receptor class A repeats which are flanked by epidermal growth factor (EGF) repeats and the spacing regions between cysteine-rich regions which are composed of  EGF and YWTD repeats.  CD91 ligands interact in part or entirely with the second and fourth cysteine-rich domains.  The β chain contains a single transmembrane domain and a short cytoplasmic tail that contains signals for endocytosis.  The two chains remain non-covalently associated with each other.  Highly orthologous molecules are found in the mouse with a 97% homology to human and in the chicken a 83% homology to human.  CD91 is a member of the LDLR supergene family, the other members are the LDLR, VLDLR and a glycoprotein of 330 kDa gp330. 

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
All ~515 kDa + 85 kDa ~515 kDa + 85 kDa 515 kDa is the a chain, 85 kDa is the b chain

POST-TRANSCRIPTIONAL MODIFICATION: No information.

POST-TRANSLATIONAL MODIFICATION

CD91 is synthized as a single chain molecule but is processed into a 2 chain molecule by cleavage in trans-Golgi by furin at a specific furin cleavage site with 3,925 aa.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD91

Some ligands expose regions rich in basic residues, which mediate binding of the ligand to acidic regions present in the cysteine-rich ligand binding repeats.  CD91 binds protease-inhibitor complexes such as protease-a2- macroglobulin complexes and complexes between the tissue-type and urinary-type plasminogen activators and plasminogen activator inhibitor type 1.  It also binds a variety of other molecules including lipoproteins, toxins, viruses and lactoferrin.  Pseudomonas exotoxin A and various heat shock proteins include gp96/GRP94, calreticulin and HSP90.  Several of the ligands do not cross-compete for binding suggesting that there are multiple binding sites on CD91. CD91 associates at a ratio of 1:2 with receptor-associated protein (RAP), a soluble 39 kDa protein which is localized to the rough endoplasmic reticulum.

Function
The role of CD91 is to mediate the uptake and elimination of ligands.  The affinity of CD91 for heat shock protein gp96 allows antigen presentatng cells to take up peptides chaperoned by gp96 for subsequent presentation to T cells.  A 40 kDa intracellular protein called receptor-associated protein (RAP) can inhibit the ligand binding to intracellular proteins in the endoplasmic reticulum while en route to the cell surface and is involved in the regulation of extracellular proteolytic activity and lipoprotein levels and provision of nutrients for the cell.  CD91 is an endocytosis-mediating receptor expressed in coated pits.  The presence of the 2 NPXY motifs in its cytoplasmic segment suggests that it may bind to and remove its many ligands from the circulation by receptor-mediated endocytosis.  

BIOCHEMICAL ACTIVITY

CD91 is an endocytic clearance receptor for lipoprotein and lipid metabolism related ligands, various proteases and protease inhibitor complexes, toxins and the amyloid precursor protein. (APP).

DISEASE RELEVANCE AND FUNCTION OF CD91 IN INTACT ANIMAL

The function of CD91 is to eliminate and mediate the uptake of its ligands.  The main role is thought to be regulation of extracellular proteolytic activity and lipoprotein levels.  The receptor has a nutritional role by its uptake of ligands.  High expression of the receptor is seen in Alzheimer plaques and in atherosclerotic lesions.  CD91 is upregulated on monocytes of patients with slow progression of advanced melanoma.  This observation maybe related to CD91-mediated internalization and cross-presentation via MHC class I pathway of tumor antigens that may maintain anti-tumor CD8+ cytotoxic T-cell responses and slow tumor progression.  There is an increased surface expression of CD91 on CD14+ monocytes of HIV-1 infected but seronegative patients correlates with apparent resistance to HIV-1.  Binding of calreticulin to CD91 complexed with surfactant proteins and associated with debris can initiate phagocytosis and pro-infammatory respinse in the lungs.  Knocking out the gene in mice is incompatibile with life.

Comments
MOLECULAR INTERACTIONS-
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD91: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD91: No information.

ADDITIONAL INSIGHTS

A phage displays antibody inhibiting the binding of pro-urokinase and partially recognizing the urokinase plasminogen activatior inhibitor complex that has been produced.
 


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
ChickenP98157X74904
HumanEntrezgene 4035Q07954
MouseX67469
Antibodies
A2MR-2   View Reactivity
A2MRa2   View Reactivity

Revised June 25, 2008


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