The Heparin/Heparan Sulfate-binding Site on Apo-serum Amyloid A

Ancsin, John B.; Kisilevsky, Robert

doi:10.1074/jbc.274.11.7172

Cited by 147 publications

(62 citation statements)

References 75 publications

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“…Various functions of SAA are linked to regions that are shown to be flexible or solvent-exposed within the hexamer and therefore may not require hexamer formation. The C terminus of human and murine SAA shows binding affinity to heparan sulfate (35), a ubiquitous component on the cell surface and within the extracellular matrix (ECM). The observation that peptides derived from the C terminus of SAA can also bind to heparan sulfate in vitro (35) suggests that hexameric SAA is not required for this interaction.…”

Section: Discussionmentioning

confidence: 99%

“…The C terminus of human and murine SAA shows binding affinity to heparan sulfate (35), a ubiquitous component on the cell surface and within the extracellular matrix (ECM). The observation that peptides derived from the C terminus of SAA can also bind to heparan sulfate in vitro (35) suggests that hexameric SAA is not required for this interaction. SAA also contains a highly conserved RGD-like adhesion motif (RGN, residues 39-41 in SAA2.2) that adheres to various cells including platelets (36).…”

Section: Discussionmentioning

confidence: 99%

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Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel

Wang

Lashuel

Walz

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Serum amyloid A (SAA) is a small apolipoprotein that binds to high-density lipoproteins in the serum. Although SAA seems to play a role in host defense and lipid transport and metabolism, its specific functions have not been defined. Despite the growing implications that SAA plays a role in the pathology of various diseases, a high-resolution structure of SAA is lacking because of limited solubility in the high-density lipoprotein-free form. In this study, complementary methods including glutaraldehyde cross-linking, size-exclusion chromatography, and sedimentationvelocity analytical ultracentrifugation were used to show that murine SAA2.2 in aqueous solution exists in a monomer-hexamer equilibrium. Electron microscopy of hexameric SAA2.2 revealed that the subunits are arranged in a ring forming a putative central channel. Limited trypsin proteolysis and mass spectrometry analysis identified a significantly protease-resistant SAA2.2 region comprising residues 39 -86. The isolated 39 -86 SAA2.2 fragment did not hexamerize, suggesting that part of the N terminus is involved in SAA2.2 hexamer formation. Circular-dichroism spectrum deconvolution and secondary-structure prediction suggest that SAA2.2 contains Ϸ50% of its residues in ␣-helical conformation and <10% in ␤-structure. These findings are consistent with the recent discovery that human SAA1.1 forms a membrane channel and have important implications for understanding the 3D structure, multiple functions, and pathological roles of this highly conserved protein.S erum amyloid A (SAA) proteins are a family of apolipoproteins found predominantly associated with high-density lipoprotein (HDL) in plasma (1), with different isoforms being unequally expressed constitutively and in response to inflammatory stimuli (2). Although synthesized primarily in the liver, extrahepatic tissue͞cellular expression of SAA has been widely documented (3). SAA has been linked to functions related to inflammation, pathogen defense, HDL metabolism, and cholesterol transport and thereby has been implicated (3) in several pathological conditions including atherosclerosis, rheumatoid arthritis, Alzheimer's disease, and cancer.SAA is known best for its role during the acute phase response to an inflammatory stimulus such as infection, tissue injury, and trauma (2). During active inflammation the concentration of SAA in plasma can increase up to 1,000-fold within 24 h (4). It is believed that persistently high levels of SAA during chronic inflammation may contribute to the occasional development of the potentially fatal disease reactive amyloidosis [amyloid A (AA) amyloidosis] (5). In AA amyloidosis, AA, an N-terminal (1-76) fragment of SAA (6), frequently is found to form amyloid deposits in the liver, kidney, and spleen. However, the presence, in vivo, of full-length SAA in amyloid deposits (7) and the ability of various SAA isoforms to form fibrils in vitro (8-10) suggest that proteolytic cleavage may not be a prerequisite for AA deposition but rather a postdeposition event. Of the thre...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel

Wang

Lashuel

Walz

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Affinity Chromatography-Heparin-agarose affinity chromatography was performed as per Ancsin and Kisilevsky (22). In brief, an 8-ml column of heparin-agarose was equilibrated with 20 mM Tris-HCl at either pH 7.5 or 5.5, as indicated.…”

Section: Methodsmentioning

confidence: 99%

“…In many cases, these interactions serve important physiological roles, but interaction of amyloidogenic precursors with heparan sulfate proteoglycans may also play an important initiating role in amyloid formation (17). Most amyloidogenic precursor proteins, including the Alzheimer's precursor protein (20,21) and serum amyloid A (SAA) (22), have been shown to have heparin binding domains that facilitate their interaction with glycosaminoglycans. These heparin binding domains usually, but not always, follow the consensus sequence for heparin binding proposed by Cardin and Weintraub (23) as follows: XBBBXXBX or XBBXBX, where B is a basic amino acid and X is a nonbasic amino acid.…”

mentioning

confidence: 99%

Identification of a Heparin Binding Domain in the N-terminal Cleavage Site of Pro-islet Amyloid Polypeptide

Park¹,

Verchere

2001

Journal of Biological Chemistry

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Islet amyloid deposits are a characteristic pathologic lesion of the pancreas in type 2 diabetes and are composed primarily of the islet beta cell peptide islet amyloid polypeptide (IAPP or amylin) as well as the basement membrane heparan sulfate proteoglycan perlecan. Impaired processing of the IAPP precursor has been implicated in the mechanism of islet amyloid formation. The Nand C-terminal cleavage sites where pro-IAPP is processed by prohormone convertases contain a series of basic amino acid residues that we hypothesized may interact with heparan sulfate proteoglycans. This possibility was tested using affinity chromatography by applying synthetic fragments of pro-IAPP to heparin-agarose and heparan sulfate-Sepharose. An N-terminal human pro-IAPP fragment (residues 1-30) was retained by both heparin-agarose and heparan sulfate-Sepharose, eluting at 0.18 M NaCl at pH 7.5. Substitution of alanine residues for two basic residues in the N-terminal cleavage site abolished heparin and heparan sulfate binding activity. At pH 5.5, the affinity of the wild-type peptide for heparin/ heparan sulfate was increased, implying a role for histidine residues at positions 6 and 28 of pro-IAPP. A Cterminal pro-IAPP fragment (residues 41-67) had no specific affinity for either heparin or heparan sulfate, and the N-or C-terminal fragments had only weak affinity for chondroitin sulfate. These data suggest that monomeric N-terminal human pro-IAPP contains a heparin binding domain that is lost during normal processing of pro-IAPP.

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“…SAA has also been reported to induce a number of other cellular responses, including collagenase production (8) and induction of secretory phospholipase A2 (9). Previously described binding properties include interaction with a number of cell types such as platelets and T cells (10,11) as well as binding to extracellular matrix glycoproteins such as laminin (11,12) and the proteoglycans heparin and heparan sulfate (13).…”

mentioning

confidence: 99%

Serum Amyloid A Protein Binds to Outer Membrane Protein A of Gram-negative Bacteria

Hari-Dass

Shah²,

Meyer

et al. 2005

Journal of Biological Chemistry

125

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Serum amyloid A (SAA) is the major acute phase protein in man and most mammals. We observed SAA binding to a surprisingly large number of Gram-negative bacteria, including Escherichia coli, Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae, Vibrio cholerae, and Pseudomonas aeruginosa. The binding was found to be high affinity and rapid. Importantly, this binding was not inhibited by high density lipoprotein with which SAA is normally complexed in serum. Binding was also observed when bacteria were offered serum containing SAA. Ligand blots following SDS-PAGE or two-dimensional gels revealed two major ligands of 29 and 35 kDa that bound SAA when probing with radiolabeled SAA or SAA and monoclonal anti-SAA. Following fractionation the ligand was found in the outer membrane fraction of E. coli and was identified by matrix-assisted laser desorption ionization time-offlight mass spectrometry to be outer membrane protein A (OmpA). OmpA-deficient E. coli did not bind SAA, and following purification of OmpA the protein retained binding activity. The ligands on other bacteria were likely to be homologues of OmpA because wild type, but not OprF-deficient, P. aeruginosa bound SAA.

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The Heparin/Heparan Sulfate-binding Site on Apo-serum Amyloid A

Cited by 147 publications

References 75 publications

Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel

Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel

Identification of a Heparin Binding Domain in the N-terminal Cleavage Site of Pro-islet Amyloid Polypeptide

Serum Amyloid A Protein Binds to Outer Membrane Protein A of Gram-negative Bacteria

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