Proteomics

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Structural basis for lipid binding and function by an evolutionally conserved protein, Serum Amyloid A


ABSTRACT: Serum amyloid A (SAA) is a plasma protein that transports lipids during inflammation. To explore SAA solution conformations and lipid binding mechanism, we used hydrogen-deuterium exchange mass spectrometry, lipoprotein reconstitution, sequence analysis and molecular dynamics simulations. Solution conformations of lipid-bound and lipid-free mSAA1 at pH~7 agreed in details with the crystal structures but also showed important differences. The results revealed that amphipathic α-helices h1 and h3 comprise a lipid-binding site that is partially pre-formed in solution, is stabilized on lipoproteins, and shows lipid-induced folding of h3. This site sequesters apolar ligands via a concave hydrophobic surface in SAA oligomers. The largely disordered C-terminal region is conjectured to mediate promiscuous binding of other ligands. The h1-h2 linker region forms an unexpected β-hairpin that may represent an early amyloidogenic intermediate. The results establish structural underpinnings for understanding SAA interactions with lipids and other ligands, its evolutional conservation, and its transition to amyloid.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: John R. Engen  

LAB HEAD: John R. Engen

PROVIDER: PXD016391 | Pride | 2020-02-17

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
SAA1_R1_10min_5deg_073118_1.raw.zip Raw
SAA1_R1_10min_5deg_080118_1.raw.zip Raw
SAA1_R1_10sec_5deg_080118_1.raw.zip Raw
SAA1_R1_10sec_5deg_080218_1.raw.zip Raw
SAA1_R1_240min_5deg_073118_1.raw.zip Raw
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Publications

Structural Basis for Lipid Binding and Function by an Evolutionarily Conserved Protein, Serum Amyloid A.

Frame Nicholas M NM   Kumanan Meera M   Wales Thomas E TE   Bandara Asanga A   Fändrich Marcus M   Straub John E JE   Engen John R JR   Gursky Olga O  

Journal of molecular biology 20200206 7


Serum amyloid A (SAA) is a plasma protein that transports lipids during inflammation. To explore SAA solution conformations and lipid-binding mechanism, we used hydrogen-deuterium exchange mass spectrometry, lipoprotein reconstitution, amino acid sequence analysis, and molecular dynamics simulations. Solution conformations of lipid-bound and lipid-free mSAA1 at pH~7.4 agreed in details with the crystal structures but also showed important differences. The results revealed that amphipathic α-heli  ...[more]

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