A role for the thiol isomerase protein ERP5 in platelet function.
Formation and rearrangement of disulfide bonds during the correct folding of nascent proteins is modulated by a family of enzymes known as thiol isomerases, which include protein disulfide isomerase (PDI), endoplasmic reticulum protein 5 (ERP5), and ERP57. Recent evidence supports an alternative role for this family of proteins on the surface of cells, where they are involved in receptor remodeling and recognition. In platelets, blocking PDI with inhibitory antibodies inhibits a number of platelet activation pathways, including aggregation, secretion, and fibrinogen binding. Analysis of human platelet membrane fractions identified the presence of the thiol isomerase protein ERP5. Further study showed that ERP5 is resident mainly on platelet intracellular membranes, although it is rapidly recruited to the cell surface in response to a range of platelet agonists. Blocking cell-surface ERP5 using inhibitory antibodies leads to a decrease in platelet aggregation in response to agonists, and a decrease in fibrinogen binding and P-selectin exposure. It is possible that this is based on the disruption of integrin function, as we observed that ERP5 becomes physically associated with the integrin beta(3) subunit during platelet stimulation. These results provide new insights into the involvement of thiol isomerases and regulation of platelet activation.
Jordan
Peter A
PA
School of Animal and Microbial Sciences, University of Reading, Whiteknights, Reading RG6 6AJ, UK.
Stevens
Joanne M
JM
Hubbard
Gary P
GP
Barrett
Natasha E
NE
Sage
Tanya
T
Authi
Kalwant S
KS
Gibbins
Jonathan M
JM
D000595:Amino Acid Sequence; D019138:Antibodies, Blocking / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology* / Q000502:physiology*; D002462:Cell Membrane / Q000201:enzymology; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D007424:Intracellular Fluid / Q000201:enzymology; D008969:Molecular Sequence Data; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*
D019138:Antibodies, Blocking; D039661:Integrin beta3; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D005340:Fibrinogen; C496931:PDIA6 protein, human; D019704:Protein Disulfide-Isomerases