4IP9

Structure of native human serum amyloid A1

Summary for 4IP9

• Entry DOI: 10.2210/pdb4ip9/pdb
• Related: 4IP8
• Descriptor: Serum amyloid A-1 protein, O-ACETALDEHYDYL-HEXAETHYLENE GLYCOL (3 entities in total)
• Functional Keywords: double layer hexameric structure, secondary amyloid, high density lipoprotein, human serum, protein binding
• Biological source: Homo sapiens (human)
• Cellular location: Secreted : P0DJI8
• Total number of polymer chains: 2
• Total formula weight: 27265.74

Authors

Lu, J.,Sun, P.D. (deposition date: 2013-01-09, release date: 2014-03-26, Last modification date: 2024-02-28)

Primary citation

Lu, J.,Yu, Y.,Zhu, I.,Cheng, Y.,Sun, P.D.
Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis.
Proc.Natl.Acad.Sci.USA, 111:5189-5194, 2014

PubMed Abstract: Serum amyloid A (SAA) represents an evolutionarily conserved family of inflammatory acute-phase proteins. It is also a major constituent of secondary amyloidosis. To understand its function and structural transition to amyloid, we determined a structure of human SAA1.1 in two crystal forms, representing a prototypic member of the family. Native SAA1.1 exists as a hexamer, with subunits displaying a unique four-helix bundle fold stabilized by its long C-terminal tail. Structure-based mutational studies revealed two positive-charge clusters, near the center and apex of the hexamer, that are involved in SAA association with heparin. The binding of high-density lipoprotein involves only the apex region of SAA and can be inhibited by heparin. Peptide amyloid formation assays identified the N-terminal helices 1 and 3 as amyloidogenic peptides of SAA1.1. Both peptides are secluded in the hexameric structure of SAA1.1, suggesting that the native SAA is nonpathogenic. Furthermore, dissociation of the SAA hexamer appears insufficient to initiate amyloidogenic transition, and proteolytic cleavage or removal of the C-terminal tail of SAA resulted in formation of various-sized structural aggregates containing ∼5-nm regular repeating protofibril-like units. The combined structural and functional studies provide mechanistic insights into the pathogenic contribution of glycosaminoglycan in SAA1.1-mediated AA amyloid formation.

PubMed: 24706838
DOI: 10.1073/pnas.1322357111

Experimental method

X-RAY DIFFRACTION (2.5 Å)