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

Frame, Nicholas M.; Kumanan, Meera; Wales, Thomas E.; Bandara, Asanga; Fändrich, Marcus; Straub, John E.; Engen, John R.; Gursky, Olga

doi:10.1016/j.jmb.2020.01.029

Cited by 16 publications

(18 citation statements)

References 62 publications

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“…(B) Cartoon showing SAA bound to HDL via h1 and h3. The h1–h3 segment is mostly α-helical in lipid-bound state at pH ~ 7, while the rest of the molecule lacks a stable structure [ 70 •]. (C) Cartoon representation of an SAA-only lipoprotein.…”

Section: X-ray Crystal Structures Reveal a Unique Protein Fold With Amentioning

confidence: 99%

“…Protein structural protection in SAA-POPC nanoparticles was measured by hydrogen-deuterium exchange mass spectrometry at several time points; darker colors indicate better-ordered regions. Bar graph shows amino acid conservation throughout evolution; taller lighter bars indicate more conserved residues (for details see [ 70 •]). Boxed region contains h2–h3 segment that is most evolutionarily conserved and is most well-ordered in lipid-bound SAA; this region contains the GPGG motif in the h2–h3 linker that defines the curvature of the concave lipid binding site formed by h1 and h3; the amphipathic character of h1 and h3 is also evolutionarily conserved [ 58 •].…”

Section: X-ray Crystal Structures Reveal a Unique Protein Fold With Amentioning

confidence: 99%

“…To explore functional conformations of SAA, hydrogen-deuterium exchange mass spectrometry was combined with circular dichroism spectroscopy and molecular dynamic simulations [ 70 •]. Lipid-free mSAA1 in solution was compared with ~ 10 nm particles reconstituted from mSAA1 and a model lipid POPC; nanoparticles such as these are often used as models of nascent HDL [ 63 , 64 ].…”

Section: Molecular Fold Of Saa Has Been Evolutionarily Conserved For mentioning

confidence: 99%

“…Remarkably, locations of the helical segments and the interhelical linkers were similar in lipid-free SAA in solution, SAA-POPC nanoparticles, and SAA crystals, despite large differences in their α-helical content. Consequently, the crystal structures depict key aspects of functional conformational ensemble of SAA and likely represent its maximally folded state [ 70 •].…”

Section: Molecular Fold Of Saa Has Been Evolutionarily Conserved For mentioning

confidence: 99%

“…1F ). Consequently, the concave hydrophobic surface in SAA has been evolutionarily conserved to sequester lipids [ 70 •].…”

Section: Molecular Fold Of Saa Has Been Evolutionarily Conserved For mentioning

confidence: 99%

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Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

Gursky

2020

Curr Atheroscler Rep

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Purpose of Review This review addresses normal and pathologic functions of serum amyloid A (SAA), an enigmatic biomarker of inflammation and protein precursor of AA amyloidosis, a life-threatening complication of chronic inflammation. SAA is a small, highly evolutionarily conserved acute-phase protein whose plasma levels increase up to one thousand-fold in inflammation, infection, or after trauma. The advantage of this dramatic but transient increase is unclear, and the complex role of SAA in immune response is intensely investigated. This review summarizes recent advances in our understanding of the structure-function relationship of this intrinsically disordered protein, outlines its newly emerging beneficial roles in lipid transport and inflammation control, and discusses factors that critically influence its misfolding in AA amyloidosis. Recent Findings High-resolution structures of lipid-free SAA in crystals and fibrils have been determined by x-ray crystallography and electron cryo-microscopy. Low-resolution structural studies of SAA-lipid complexes, together with biochemical, cell-based, animal model, genetic, and clinical studies, have provided surprising new insights into a wide range of SAA functions. An emerging vital role of SAA is lipid encapsulation to remove cell membrane debris from sites of injury. The structural basis for this role has been proposed. The lysosomal origin of AA amyloidosis has solidified, and its molecular and cellular mechanisms have emerged. Summary Recent studies have revealed molecular underpinnings for understanding complex functions of this Cambrian protein in lipid transport, immune response, and amyloid formation. These findings help guide the search for much-needed targeted therapies to block the protein deposition in AA amyloidosis.

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Section: X-ray Crystal Structures Reveal a Unique Protein Fold With Amentioning

confidence: 99%

Section: X-ray Crystal Structures Reveal a Unique Protein Fold With Amentioning

confidence: 99%

Section: Molecular Fold Of Saa Has Been Evolutionarily Conserved For mentioning

confidence: 99%

Section: Molecular Fold Of Saa Has Been Evolutionarily Conserved For mentioning

confidence: 99%

“…1F ). Consequently, the concave hydrophobic surface in SAA has been evolutionarily conserved to sequester lipids [ 70 •].…”

Section: Molecular Fold Of Saa Has Been Evolutionarily Conserved For mentioning

confidence: 99%

See 3 more Smart Citations

Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

Gursky

2020

Curr Atheroscler Rep

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High-Density Lipoproteins and Serum Amyloid A (SAA)

Webb

2021

Curr Atheroscler Rep

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Purpose of Review Serum amyloid A (SAA) is a highly sensitive acute phase reactant that has been linked to a number of chronic inflammatory diseases. During a systemic inflammatory response, liver-derived SAA is primarily found on high-density lipoprotein (HDL). The purpose of this review is to discuss recent literature addressing the pathophysiological functions of SAA and the significance of its association with HDL. Recent Findings Studies in gene-targeted mice establish that SAA contributes to atherosclerosis and some metastatic cancers. Accumulating evidence indicates that the lipidation state of SAA profoundly affects its bioactivities, with lipid-poor, but not HDL-associated, SAA capable of inducing inflammatory responses in vitro and in vivo. Factors that modulate the equilibrium between lipid-free and HDL-associated SAA have been identified. Summary HDL may serve to limit SAA’s bioactivities in vivo. Understanding the factors leading to the release of systemic SAA from HDL may provide insights into chronic disease mechanisms.

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Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis

Lewkowicz

Gursky

2022

Biophysical Chemistry

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

Cited by 16 publications

References 62 publications

Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

High-Density Lipoproteins and Serum Amyloid A (SAA)

Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis

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