C-reactive protein (L8) Flashcards
What are the types of serum pentraxins?
CRP, serum amyloid P-component (SAP), pentraxins and lectins
What happens to CRP in the acute-phase?
An acute phase reactant which increases in serum concentration of up to 100-fold in response to infection and injury
What happens to CRP during complement activation?
When bound to a suitable ligand, CRP binds C1q and activates complement via the classical pathway
What happens to CRP during immune clearance?
CRP recognises receptors on immune cells leading to clearance of bound ligands
What is CRP used as a clinical indicator of?
Tissue infection, injury and inflammation?
How is CRP implicated in autoimmune disease?
Recognition and removal of nuclear debris prevents generation of autoantibodies
What are the features of human SAP?
A trace plasma protein
Exhibits small increase in concentration in the acute phase
Exhibits lectin-like binding to carbohydrate in addition to phospoethanolamine
Thought to be major Ca-dependent DNA binding protein in the serum
Constituent of amyloid deposits
What are the binding properties of CRP and what does it bind?
Ca-dependent cell surface recognition of phosphocholine on phospholipids of damaged cell and on foreign pathogens
C1q (complement)
Nuclear debris
IgG receptor Fcgamma R on immune cells
What are the binding properties of SAP?
Ca-dependent recognition of phosphoethanolamine Some carbs (Lectin-like)
What are the aggregation structures of Human CRP and SAP?
Pentraxin helix on one pentamer face, calcium binding sites on the other face
Interprotomer contacts include salt bridges which differ between CRP and SAP
Protomers in SAP pentamer ‘twisted’ with respect to CRP protomer
How does human CRP bind to ligands?
5 Calcium dependent ligand binding sites on one pentameric face leading to multivalent recognition
Two calcium ions in each protomer, coordinated by Asp60, Asn61, Glu138, Asp140, Glu147 and Gln150
How is PC-binding defined in human CRP?
Phosphate coordination to calcium ions
Glu81 (Lys in SAP) interacts with positively carged amine
Phe66 (Tyr in SAP) defines the hydrophobic pocket
What residues are important in complement activation by CRP/SAP?
D112-important in c1q site
H38R
Y175A- stops c1q binding and complement activation
E88 and K114 also important for c1q binding site
Why is Human SAP targeted in the treatment of amyloidosis?
Sap binds to fibrils in all types of amyloid deposits, and contributes to pathogenesis
SAP is highly reistant to proteolysis and it is though that Ca-dependent binding of SAP to amyloid fibrils protects them from degradation
Describe the CPHPC complec with human SAP
CPHPC carboxylates bind in the Ca-dep ligand binding pocket
CPHPC crosslinks and dimerises SAP molecules, leading to their very rapid clearance by the liver, reduces circulating SAP
Drug action removes SAP from amyloid deposits