Ligand-assisted aggregation of proteins. Dimerization of serum amyloid P component by bivalent ligands.
A comprehensive series of solution and crystallographic studies reveal how simple, achiral, bivalent ligands of the cyclic pyruvate of glycerol promote face-to-face complex formation of the pentraxin, serum amyloid P component (SAP) into decamers. SAP, a protein of the human innate immune system, is universally present in amyloids, including cerebral amyloid deposits found in the brain of Alzheimer disease patients. Removal of SAP through a specific aggregation mechanism mediated by multivalent ligands appears to provide therapeutic benefit in the progression of this disease. Crystallographic studies reveal that in our novel series of ligands only the methyl and carboxylate moieties of the pyruvate ketal directly interact with the protein, but the geometric constraints imposed by the tether dictate which of two chair conformations are adopted by the pyruvate dioxane ring. Solution studies, as interpreted through a simple thermodynamic model, account for the distribution of pentameric and decameric bound states at different ligand concentrations and indicate that differences in the flexibility of the tether determine the geometry and stability of the specific aggregates formed between SAP and two different bivalent ligands. The factors affecting the design of ligands promoting face-to-face protein dimerization as well as potential biological implications are discussed.
Ho
Jason G S
JG
Department of Biological Sciences, University of Calgary, Alberta, Canada.
Kitov
Pavel I
PI
Paszkiewicz
Eugenia
E
Sadowska
Joanna
J
Bundle
David R
DR
Ng
Kenneth K-S
KK
D018360:Crystallography, X-Ray; D003838:Deoxyadenine Nucleotides / Q000737:chemistry; D019281:Dimerization; D006801:Humans; D008024:Ligands; D017434:Protein Structure, Tertiary; D000683:Serum Amyloid P-Component / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D003838:Deoxyadenine Nucleotides; D008024:Ligands; D000683:Serum Amyloid P-Component; C012873:2'-deoxy-5'-adenosine monophosphate